Is MTMR2 p.Ser47Pro (c.139T>C) pathogenic?

MTMR2 p.Ser47Pro (c.139T>C) is classified Uncertain significance in MTMR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-29). AlphaMissense: likely benign (0.0955); Very rare (popmax 0.00348%, nfe); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with MTMR2 p.Ser47Pro (c.139T>C)?

MTMR2 p.Ser47Pro (c.139T>C) is associated with Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease (ClinVar).

How common is MTMR2 p.Ser47Pro (c.139T>C) in the general population?

MTMR2 p.Ser47Pro (c.139T>C) is very rare (popmax 0.00348%, nfe) (gnomAD).

What do computational predictors say about MTMR2 p.Ser47Pro (c.139T>C)?

AlphaMissense predicts likely benign (score 0.0955) — an in-silico prediction, not a clinical call.

MTMR2 p.Ser47Pro

c.139T>C · rs372095826 · VCV916797

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0955 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00348%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.0955	likely benign
REVEL	0.384	indeterminate
SaProt	LLR -8.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 47 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	22.8	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 0.00348% European (non-Finnish) · 41/1,179,746 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.0026% 42/1,613,534 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00348%	28,774
Remaining individualsnot grpmax-eligible	0.0016%	62,458

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.Ser47Pro
Coding: c.139T>C
MANE Select: NM_016156
dbSNP: rs372095826
Type: single nucleotide variant
Location: chr11:95888203 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.44 · 5 PDB
Residue 47: 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

Also linked: Charcot-Marie-Tooth disease

Similar variants

MTMR2 p.Ser47= 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-ser47pro (accessed [today's date]).

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