Is SH3TC2 p.Ala1237Val (c.3710C>T) pathogenic?

SH3TC2 p.Ala1237Val (c.3710C>T) is classified Uncertain significance in SH3TC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-09). AlphaMissense: likely pathogenic (0.6817); Very rare (popmax 0.00891%, eas); Associated with Charcot-Marie-Tooth disease type 4C.

What condition is associated with SH3TC2 p.Ala1237Val (c.3710C>T)?

SH3TC2 p.Ala1237Val (c.3710C>T) is associated with Charcot-Marie-Tooth disease type 4C, susceptibility to mononeuropathy of the median nerve, mild, Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is SH3TC2 p.Ala1237Val (c.3710C>T) in the general population?

SH3TC2 p.Ala1237Val (c.3710C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

How is Charcot-Marie-Tooth disease type 4C inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SH3TC2 p.Ala1237Val (c.3710C>T)?

AlphaMissense predicts likely pathogenic (score 0.6817) — an in-silico prediction, not a clinical call.

SH3TC2 p.Ala1237Val

c.3710C>T · rs778953792 · VCV1491635

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4C

Computational evidence

Protein change
AlphaMissense	0.6817	likely pathogenic
REVEL	0.759	pathogenic-leaning
SaProt	LLR -15.17	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 22 kb · p 0.41 · regional, not allelic
Overall
CADD	30.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,896 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000248% 4/1,614,070 alleles · very rare exomes 3/1,461,894 · genomes 1/152,176 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SH3TC2
Protein: p.Ala1237Val
Coding: c.3710C>T
MANE Select: NM_024577
dbSNP: rs778953792
Type: single nucleotide variant
Location: chr5:149004868 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.63
Residue 1237: a UniProt-annotated variant site (in cmt4c)

Full SH3TC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 4C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: susceptibility to mononeuropathy of the median nerve, mild Charcot-Marie-Tooth disease type 4

For Charcot-Marie-Tooth disease type 4C (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

SH3TC2 c.1178-1G>A Pathogenic/Likely pathogenic ★★ same condition
SH3TC2 c.3676-8G>A Pathogenic/Likely pathogenic ★★ same condition
SH3TC2 c.386-2A>C Pathogenic/Likely pathogenic ★★ same condition
SH3TC2 c.53-2A>G Likely pathogenic ★★ same condition
SH3TC2 c.805+2T>C Pathogenic/Likely pathogenic ★★ same condition
SH3TC2 p.Arg1052Ter Pathogenic ★★ same condition
SH3TC2 p.Arg1109Ter Pathogenic ★★ same condition
SH3TC2 p.Arg1171Cys Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/sh3tc2-p-ala1237val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown