Is MTMR2 c.357+4A>C pathogenic?

MTMR2 c.357+4A>C is classified Uncertain significance in MTMR2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-07-19). Very rare (popmax 0.00241%, nfe); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with MTMR2 c.357+4A>C?

MTMR2 c.357+4A>C is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is MTMR2 c.357+4A>C in the general population?

MTMR2 c.357+4A>C is very rare (popmax 0.00241%, nfe) (gnomAD).

MTMR2 c.357+4A>C

rs863224750 · VCV216646

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00241%, nfe)

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
Splice region	donor +4	donor splice region (+4, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	Δ0.66	donor loss, 4 bp away · masked 0 · deltas
Pangolin	Δ0.46	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5	GERP 2.2, phastCons 1
Non-coding constraint	Z 2.08	1 kb window · o/e 0.84 · regional · uncalibrated
Overall
CADD	13.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00241% European (non-Finnish) · 28/1,161,798 alleles

Filtering AF 0.00167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00144%

Overall 0.00194% 28/1,440,756 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
Coding: c.357+4A>C
MANE Select: NM_016156
dbSNP: rs863224750
Type: single nucleotide variant
Location: chr11:95862268 (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

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-c-357-plus-4a-c (accessed [today's date]).

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