Is MTMR2 p.His416= (c.1248T>C) pathogenic?

MTMR2 p.His416= (c.1248T>C) is classified Likely benign in MTMR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-30). Ultra-rare (popmax 0.0165%, mid); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with MTMR2 p.His416= (c.1248T>C)?

MTMR2 p.His416= (c.1248T>C) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is MTMR2 p.His416= (c.1248T>C) in the general population?

MTMR2 p.His416= (c.1248T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

MTMR2 p.His416=

c.1248T>C · rs779618687 · VCV1626162

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.81	GERP -5.6
Overall
CADD	0.609	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.00105% 17/1,614,000 alleles · ultra-rare exomes 14/1,461,698 · genomes 3/152,302 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0032%	31,250
East Asian	0.00223%	44,880
Admixed American	0.00167%	59,980
South Asian	0.0011%	91,082
European (non-Finnish)	0.000932%	107,265

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.His416=
Coding: c.1248T>C
MANE Select: NM_016156
dbSNP: rs779618687
Type: single nucleotide variant
Location: chr11:95845091 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.44 · 5 PDB
Residue 416: the myotubularin phosphatase 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-his416 (accessed [today's date]).

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