Is MTMR2 p.Glu136Asp (c.408A>C) pathogenic?

MTMR2 p.Glu136Asp (c.408A>C) is classified Uncertain significance in MTMR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-27). AlphaMissense: likely pathogenic (0.6992); Very rare (popmax 0.000509%, nfe); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with MTMR2 p.Glu136Asp (c.408A>C)?

MTMR2 p.Glu136Asp (c.408A>C) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is MTMR2 p.Glu136Asp (c.408A>C) in the general population?

MTMR2 p.Glu136Asp (c.408A>C) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about MTMR2 p.Glu136Asp (c.408A>C)?

AlphaMissense predicts likely pathogenic (score 0.6992) — an in-silico prediction, not a clinical call.

MTMR2 p.Glu136Asp

c.408A>C · rs1555065024 · VCV543337

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.6992	likely pathogenic
REVEL	0.585	indeterminate
SaProt	LLR -10.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -0.071, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 47 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	23.5	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 0.000509% European (non-Finnish) · 6/1,179,926 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,648 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.Glu136Asp
Coding: c.408A>C
MANE Select: NM_016156
dbSNP: rs1555065024
Type: single nucleotide variant
Location: chr11:95862052 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.44 · 5 PDB
Residue 136: the gram domain; a β-strand

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-glu136asp (accessed [today's date]).

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