Is MTMR2 p.Val44Ala (c.131T>C) pathogenic?

MTMR2 p.Val44Ala (c.131T>C) is classified Uncertain significance in MTMR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-17). AlphaMissense: likely benign (0.0668); Very rare (popmax 0.004%, afr); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with MTMR2 p.Val44Ala (c.131T>C)?

MTMR2 p.Val44Ala (c.131T>C) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is MTMR2 p.Val44Ala (c.131T>C) in the general population?

MTMR2 p.Val44Ala (c.131T>C) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about MTMR2 p.Val44Ala (c.131T>C)?

AlphaMissense predicts likely benign (score 0.0668) — an in-silico prediction, not a clinical call.

MTMR2 p.Val44Ala

c.131T>C · rs375382954 · VCV2188497

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0668 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.0668	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.45	unconstrained · MANE · 36 kb · p 0.00085 · regional, not allelic
Overall
CADD	18.37	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.004% African / African-American · 3/74,920 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,590 alleles · very rare exomes 2/1,461,380 · genomes 1/152,210 · 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: MTMR2
Protein: p.Val44Ala
Coding: c.131T>C
MANE Select: NM_016156
dbSNP: rs375382954
Type: single nucleotide variant
Location: chr11:95888211 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.44 · 5 PDB
Residue 44: the 'disordered' region

Full MTMR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

MTMR2 p.Val44Ile Benign/Likely benign ★★ same residue
MTMR2 c.804+2T>G Likely pathogenic ★★ same condition
MTMR2 p.Arg162Ter Pathogenic ★★ same condition
MTMR2 p.Arg364Ter Pathogenic ★★ same condition
MTMR2 p.Glu531Ter Pathogenic ★★ same condition
MTMR2 p.Glu574Ter Pathogenic/Likely pathogenic ★★ same condition
MTMR2 c.262+4C>T Uncertain significance ★★ same condition
MTMR2 p.Ala397Gly Uncertain significance ★★ ⚠ 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/mtmr2-p-val44ala (accessed [today's date]).

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