Is MTMR2 p.Arg586Trp (c.1756C>T) pathogenic?

MTMR2 p.Arg586Trp (c.1756C>T) is classified Uncertain significance in MTMR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-27). AlphaMissense: ambiguous (0.4541); Very rare (popmax 0.00446%, eas); Associated with Charcot-Marie-Tooth disease type 4.

What condition is associated with MTMR2 p.Arg586Trp (c.1756C>T)?

MTMR2 p.Arg586Trp (c.1756C>T) is associated with Charcot-Marie-Tooth disease type 4 (ClinVar).

How common is MTMR2 p.Arg586Trp (c.1756C>T) in the general population?

MTMR2 p.Arg586Trp (c.1756C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about MTMR2 p.Arg586Trp (c.1756C>T)?

AlphaMissense predicts ambiguous (score 0.4541) — an in-silico prediction, not a clinical call.

MTMR2 p.Arg586Trp

c.1756C>T · rs61735577 · VCV2189221

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4541 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Charcot-Marie-Tooth disease type 4

Computational evidence

Protein change
AlphaMissense	0.4541	ambiguous
REVEL	0.692	pathogenic-leaning
SaProt	LLR -9.66	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.4	GERP -2.6, phastCons 0.87
Regional constraint	o/e 1.01	unconstrained · MANE · 6,365 bp · p 0.92 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,846 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000411% 6/1,460,660 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,423
South Asian	0.0022%	45,522
European (non-Finnish)	0.00017%	589,449

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.Arg586Trp
Coding: c.1756C>T
MANE Select: NM_016156
dbSNP: rs61735577
Type: single nucleotide variant
Location: chr11:95836162 (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 p.Arg586= Benign ★★ same residue
MTMR2 p.Arg586Gln Likely benign ★★ same residue
MTMR2 p.Arg586Gly Uncertain significance ★ ⚠ 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

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-arg586trp (accessed [today's date]).

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