Is MTMR1 p.Pro583Ala (c.1747C>G) pathogenic?

MTMR1 p.Pro583Ala (c.1747C>G) is classified Uncertain significance in MTMR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: ambiguous (0.4552); Ultra-rare (popmax 0.0141%, afr).

How common is MTMR1 p.Pro583Ala (c.1747C>G) in the general population?

MTMR1 p.Pro583Ala (c.1747C>G) is ultra-rare (popmax 0.0141%, afr) (gnomAD).

What do computational predictors say about MTMR1 p.Pro583Ala (c.1747C>G)?

AlphaMissense predicts ambiguous (score 0.4552) — an in-silico prediction, not a clinical call.

MTMR1 p.Pro583Ala

c.1747C>G · rs368905816 · VCV2475577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4552 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0141%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4552	ambiguous
REVEL	0.822	moderately pathogenic-leaning
SaProt	LLR -8.06	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 69 kb · p 8.4e-10 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P575A vs ClinVar P583A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0141% African / African-American · 8/56,783 alleles

Filtering AF 0.00694% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00506%

Overall 0.000665% 8/1,203,417 alleles · ultra-rare exomes 4/1,092,111 · genomes 4/111,306 · 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: MTMR1
Protein: p.Pro583Ala
Coding: c.1747C>G
MANE Select: NM_001306144
dbSNP: rs368905816
Type: single nucleotide variant
Location: chrX:150755755 (GRCh38)
Structure: AlphaFold pLDDT 85.72 · 1 PDB
Residue 575 UniProt numbering: the myotubularin phosphatase domain

Full MTMR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MTMR1 c.1081-305A>G Benign ★★ same type
MTMR1 c.1081-4G>A Benign ★★ same type
MTMR1 c.277-41C>T Benign ★★ same type
MTMR1 c.448-137G>A Benign ★★ same type
MTMR1 p.Gly642= Benign ★★ same type
MTMR1 c.253-1G>T Uncertain significance ★ same type
MTMR1 p.Ala116Val Uncertain significance ★ ⚠ same type
MTMR1 p.Ala223Ser Uncertain significance ★ ⚠ same type

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/mtmr1-p-pro583ala (accessed [today's date]).

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