Is MTMR2 p.Ser455fs (c.1362_1363del) pathogenic?

MTMR2 p.Ser455fs (c.13621363del) is classified Pathogenic/Likely pathogenic in MTMR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-07). Very rare (popmax 8.48e-05%, nfe); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with MTMR2 p.Ser455fs (c.1362_1363del)?

MTMR2 p.Ser455fs (c.1362_1363del) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is MTMR2 p.Ser455fs (c.1362_1363del) in the general population?

MTMR2 p.Ser455fs (c.1362_1363del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

MTMR2 p.Ser455fs

c.1362_1363del · rs1177373744 · VCV944156

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,712 alleles

Overall 6.2e-05% 1/1,613,564 alleles · very rare exomes 0/1,461,422 · genomes 1/152,142 · joint denominator

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.Ser455fs
Coding: c.1362_1363del
MANE Select: NM_016156
dbSNP: rs1177373744
Type: Deletion
Location: chr11:95844976 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.44 · 5 PDB
Residue 455: the myotubularin phosphatase domain; an α-helix

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 p.Ser455Arg Uncertain significance ★★ ⚠ same residue
MTMR2 p.Ser455Asn Uncertain significance ★ ⚠ same residue
MTMR2 p.Lys256fs Pathogenic/Likely pathogenic ★★ same condition
MTMR2 p.Val639fs Uncertain significance ★★ same condition
MTMR2 c.1770+7_1770+12del Benign/Likely benign ★★ same condition
MTMR2 p.Arg62del Benign/Likely benign ★★ same condition
MTMR2 c.1479+1_1479+2del Likely pathogenic ★ same condition
MTMR2 p.Asn345fs Pathogenic ★ 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-ser455fs (accessed [today's date]).

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