Is MTMR2 p.Ser277Arg (c.829A>C) pathogenic?

MTMR2 p.Ser277Arg (c.829A>C) is classified Uncertain significance in MTMR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-03). AlphaMissense: likely pathogenic (0.9949); Very rare (popmax 0.00167%, amr); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with MTMR2 p.Ser277Arg (c.829A>C)?

MTMR2 p.Ser277Arg (c.829A>C) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is MTMR2 p.Ser277Arg (c.829A>C) in the general population?

MTMR2 p.Ser277Arg (c.829A>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MTMR2 p.Ser277Arg (c.829A>C)?

AlphaMissense predicts likely pathogenic (score 0.9949) — an in-silico prediction, not a clinical call.

MTMR2 p.Ser277Arg

c.829A>C · rs779257949 · VCV661479

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9949 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.9949	likely pathogenic · top 7% in MTMR2
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -9.83	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.22 · evaluated, not missing
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	27.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,014 alleles

Overall 0.000186% 3/1,614,132 alleles · very rare exomes 3/1,461,812 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,254
Admixed Americangrpmax	0.00167%	60,014

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser277Arg
Coding: c.829A>C
MANE Select: NM_016156
dbSNP: rs779257949
Type: single nucleotide variant
Location: chr11:95849838 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.44 · 5 PDB
Residue 277: the myotubularin phosphatase domain; a turn

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-ser277arg (accessed [today's date]).

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