Is MTMR2 p.Pro202Ala (c.604C>G) pathogenic?

MTMR2 p.Pro202Ala (c.604C>G) is classified Uncertain significance in MTMR2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-07). AlphaMissense: likely benign (0.0652); Ultra-rare (popmax 0.0451%, sas); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with MTMR2 p.Pro202Ala (c.604C>G)?

MTMR2 p.Pro202Ala (c.604C>G) is associated with Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease type 4B1, Charcot-Marie-Tooth disease (ClinVar).

How common is MTMR2 p.Pro202Ala (c.604C>G) in the general population?

MTMR2 p.Pro202Ala (c.604C>G) is ultra-rare (popmax 0.0451%, sas) (gnomAD).

What do computational predictors say about MTMR2 p.Pro202Ala (c.604C>G)?

AlphaMissense predicts likely benign (score 0.0652) — an in-silico prediction, not a clinical call.

MTMR2 p.Pro202Ala

c.604C>G · rs186380748 · VCV543380

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0652 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0451%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.0652	likely benign
REVEL	0.333	indeterminate
SaProt	LLR -7.70	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 47 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	17.67	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 0.0451% South Asian · 41/91,008 alleles

Filtering AF 0.0341% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.0278% 448/1,612,234 alleles · ultra-rare exomes 422/1,460,358 · genomes 26/151,876 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0451%	2,220
Middle Eastern	0.0331%	3,018
European (non-Finnish)	0.0321%	3,119
Remaining individualsnot grpmax-eligible	0.0192%	5,203
Admixed American	0.0167%	5,998
African / African-American	0.00534%	18,709
Finnishnot grpmax-eligible	0.00156%	63,912

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.Pro202Ala
Coding: c.604C>G
MANE Select: NM_016156
dbSNP: rs186380748
Type: single nucleotide variant
Location: chr11:95857602 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.44 · 5 PDB

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

Also linked: Charcot-Marie-Tooth disease type 4B1 Charcot-Marie-Tooth disease

Similar variants

MTMR2 c.804+2T>G Likely pathogenic ★★ same condition
MTMR2 p.Arg102Ter Pathogenic/Likely pathogenic ★★ same condition
MTMR2 p.Arg162Ter Pathogenic ★★ same condition
MTMR2 p.Arg364Ter Pathogenic ★★ same condition
MTMR2 p.Gln590Ter 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

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-pro202ala (accessed [today's date]).

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