Is MTMR2 p.Glu450Val (c.1349A>T) pathogenic?

MTMR2 p.Glu450Val (c.1349A>T) is classified Uncertain significance in MTMR2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-03-18). AlphaMissense: likely pathogenic (0.8756); Very rare (popmax 0.000593%, nfe); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with MTMR2 p.Glu450Val (c.1349A>T)?

MTMR2 p.Glu450Val (c.1349A>T) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is MTMR2 p.Glu450Val (c.1349A>T) in the general population?

MTMR2 p.Glu450Val (c.1349A>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about MTMR2 p.Glu450Val (c.1349A>T)?

AlphaMissense predicts likely pathogenic (score 0.8756) — an in-silico prediction, not a clinical call.

MTMR2 p.Glu450Val

c.1349A>T · rs1263941266 · VCV1929380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.8756	likely pathogenic
REVEL	0.96	strongly pathogenic-leaning
SaProt	LLR -15.24	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 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 47 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	29.3	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 0.000593% European (non-Finnish) · 7/1,179,840 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,798 alleles · very rare

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.Glu450Val
Coding: c.1349A>T
MANE Select: NM_016156
dbSNP: rs1263941266
Type: single nucleotide variant
Location: chr11:95844990 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.44 · 5 PDB
Residue 450: the myotubularin phosphatase domain; an α-helix

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 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
MTMR2 p.Ala497Thr 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-glu450val (accessed [today's date]).

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