What Happened to CMT2A1? KIF1B and the Disputed Rating

On October 19, 2026, the ClinGen Charcot-Marie-Tooth expert panel rated the link between the gene KIF1B and Charcot-Marie-Tooth disease type 2A1 (CMT2A1) as Disputed. To put it simply, the panel now disputes the proposed link between KIF1B and CMT2A1, because the evidence rested on a very small number of people and has not held up on review.

This is a step down from the panel’s earlier verdict. The same link was rated Limited with a classification date of June 12, 2026, according to the ClinGen data file the table I downloaded on October 13. ClinGen’s own website shows only the current record, so that file is the evidence for the earlier rating.¹ Their table’s November 3 refresh introduced the new Disputed designation.

My Open CMT Gene Table on GitHub now shows KIF1B as Disputed, and its changelog records the change. The same data is mirrored on the simpler table here on cmt.blog.

Why CMT2A1 Pointed at KIF1B

The “2A” in CMT2A is an older labeling scheme: axonal CMT (type 2) was sorted into lettered subtypes, and some of those letters began as labels for regions of a chromosome rather than for genes. In 2001, researchers described a Japanese family with dominantly inherited axonal CMT, which they called CMT2A, and a variant in KIF1B (Zhao et al., PMID 11389829).² KIF1B is a motor protein that moves cargo along nerve fibers, so it was a sensible suspect, and ClinGen now files the proposed KIF1B association under the label CMT2A1.

The same family had earlier been linked to a stretch of chromosome 1 (1p36.2; Saito et al., PMID 9409358). That region also holds MFN2, a different gene. In 2004 MFN2 variants were found in seven families with CMT2A, which made MFN2 the main gene for that subtype (Züchner et al., PMID 15064763). Later work confirmed it as a common cause: one study found MFN2 variants in about a third of familial CMT2 cases (Verhoeven et al., PMID 16714318).³ CMT2A2A is an older term for that MFN2 disease.

Why the Panel Called It Disputed

ClinGen’s curation for KIF1B and CMT2A1 gives three reasons, in its own summary:

1. One family only. The panel found no convincing independent replication, so the overall evidence had not been upheld over time.
2. MFN2 was not excluded. In the 2004 study, seven other families with CMT2A carried MFN2 variants and no KIF1B mutations, and ClinGen’s review says MFN2 variants were not excluded in the original family.
3. Common variants. Other reported KIF1B variants (PMIDs 30126838 and 25802885) are too frequent in the general population to add genetic support for the link.⁴

The panel did credit the laboratory evidence. KIF1B does take part in axonal transport, and mice with one working copy developed an axonal neuropathy by 12 months. That makes KIF1B biologically plausible, but plausible is not the same as proven. Under ClinGen’s rules, Disputed can mean that the original evidence is unconvincing, that other evidence conflicts with it, or both; here, the original single-family evidence has not held up.

If You Have an Older CMT2A1 or KIF1B Label

A documented neuropathy remains real while its attribution to KIF1B is disputed.

This is general information, not medical advice. Anyone holding a genetic report or a diagnosis that names KIF1B or CMT2A1 can take it to a clinician or genetic counselor to review.

What the rating change does and doesn’t say:

• It says the gene-disease link is no longer supported by ClinGen’s panel. Labs may consult ClinGen’s gene-disease assessment when they evaluate a KIF1B finding for CMT.
• It does not say anyone’s neuropathy is not real. A person’s documented neuropathy remains real while its attribution to KIF1B is disputed; the open question is which gene, if any, explains it.
• A clinician or genetic counselor can help you ask whether your lab has re-evaluated the result.

The label itself can mislead, too. The original 2001 and 2004 papers both used the label “CMT2A” for different genetic explanations, so an older report may mean KIF1B or MFN2 by it. CMT2A2A is a historical term for dominant MFN2 disease; GeneReviews now uses MFN2-HMSN.

One more caution: ClinGen’s curation text describes the original family’s variant as likely pathogenic, but its scoring gives that family zero counted genetic points. An older report with that wording is not a current interpretation of anyone’s own variant.

How the Table Keeps Track

The Open CMT Gene Table refreshes monthly from ClinGen, Mondo, GeneReviews and PanelApp, and each refresh is reviewed before it is merged. Every change gets a dated line in the changelog, so a rating that moves, as KIF1B just did, can be traced. In the data, the curation_subtype_names column is specific to each ClinGen curation, while a separate historical_subtype_names column is explicitly gene-wide. For KIF1B, PanelApp’s Genomics England and Australia panels both rated the gene Red when checked on November 8, 2026.⁵

When you cite the table, link a tagged release (for example v2026.11) rather than the latest files, so readers see the ratings as they stood on that date.

That release now exists: v2026.11 carries the data files with KIF1B shown as Disputed. Its Zenodo archive, 10.5281/zenodo.24067693, is the citable copy of that exact version, and the concept DOI always resolves to the latest version.

Notes

1. ClinGen’s data file was downloaded on October 13, 2026 and committed to the table’s repository as data/clingen-cmt.csv; the KIF1B row is in commit f29ad99. ClinGen’s page also shows a line about a calculated versus a modified classification. That is a scoring note, not the earlier published rating. ↩︎
2. Zhao et al., “Charcot-Marie-Tooth Disease Type 2A Caused by Mutation in a Microtubule Motor KIF1Bβ,” Cell 105, no. 5 (2001): 587–97; Saito et al., Neurology 49, no. 6 (1997): 1630–35. ↩︎
3. Züchner et al., Nature Genetics 36, no. 5 (2004): 449–51; Verhoeven et al., Brain 129 (2006): 2093–102. ↩︎
4. Xu et al., Journal of Cell Biology 217, no. 10 (2018): 3480–96 (PMID 30126838), and Drew et al., Molecular Genetics & Genomic Medicine 3, no. 2 (2015): 143–54 (PMID 25802885): the two reports ClinGen’s summary cites. ↩︎
5. Genomics England PanelApp panel 846 and PanelApp Australia panel 3070, both checked on November 8, 2026. ↩︎

Sources

• ClinGen Charcot-Marie-Tooth Disease Gene Curation Expert Panel. “Gene-disease validity: KIF1B and Charcot-Marie-Tooth disease type 2A1 (CCID:005229), Disputed.” ClinGen Clinical Genome Resource. October 19, 2026. https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ae6ffeae-9609-47bf-89a9-4863cf6ef05c-2026-10-19T160000.000Z.
• Drew, Alexander P, Danqing Zhu, Aditi Kidambi, et al. “Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing.” Molecular genetics & genomic medicine 3, no. 2 (2015): 143–54. https://doi.org/10.1002/mgg3.126.
• Knauss, Dan. Open CMT Gene Table, release v2026.11. Zenodo, 2026. https://doi.org/10.5281/zenodo.24067693.
• Saito, M, Y Hayashi, T Suzuki, H Tanaka, I Hozumi, and S Tsuji. “Linkage mapping of the gene for Charcot-Marie-Tooth disease type 2 to chromosome 1p (CMT2A) and the clinical features of CMT2A.” Neurology 49, no. 6 (1997): 1630–5. https://doi.org/10.1212/wnl.49.6.1630.
• Verhoeven, Kristien, Kristl G Claeys, Stephan Züchner, et al. “MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2.” Brain : a journal of neurology 129, no. Pt 8 (2006): 2093–102. https://doi.org/10.1093/brain/awl126.
• Xu, Fang, Hironori Takahashi, Yosuke Tanaka, et al. “KIF1Bβ mutations detected in hereditary neuropathy impair IGF1R transport and axon growth.” The Journal of cell biology 217, no. 10 (2018): 3480–3496. https://doi.org/10.1083/jcb.201801085.
• Zhao, C, J Takita, Y Tanaka, et al. “Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta.” Cell 105, no. 5 (2001): 587–97. https://doi.org/10.1016/s0092-8674(01)00363-4.
• Züchner, Stephan. “MFN2 Hereditary Motor and Sensory Neuropathy.” In GeneReviews®. University of Washington, Seattle, 2025. https://www.ncbi.nlm.nih.gov/books/NBK1511/.
• Züchner, Stephan, Irina V Mersiyanova, Maria Muglia, et al. “Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.” Nature genetics 36, no. 5 (2004): 449–51. https://doi.org/10.1038/ng1341.