Is TRPM1 p.Arg577Trp (c.1729C>T) pathogenic?

TRPM1 p.Arg577Trp (c.1729C>T) is classified Uncertain significance in TRPM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-27). AlphaMissense: likely pathogenic (0.9556); Ultra-rare (popmax 0.0107%, afr).

How common is TRPM1 p.Arg577Trp (c.1729C>T) in the general population?

TRPM1 p.Arg577Trp (c.1729C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about TRPM1 p.Arg577Trp (c.1729C>T)?

AlphaMissense predicts likely pathogenic (score 0.9556) — an in-silico prediction, not a clinical call.

TRPM1 p.Arg577Trp

c.1729C>T · rs373261110 · VCV1481747

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9556 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9556	likely pathogenic
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -15.94	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP -0.49, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 53 kb · p 0.68 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R555W vs ClinVar R577W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,940 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00229% 37/1,614,102 alleles · ultra-rare exomes 34/1,461,894 · genomes 3/152,208 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,368
European (non-Finnish)	0.00237%	42,145
Admixed American	0.00167%	60,010

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: TRPM1
Protein: p.Arg577Trp
Coding: c.1729C>T
MANE Select: NM_001252024
dbSNP: rs373261110
Type: single nucleotide variant
Location: chr15:31047146 (GRCh38)
Gene constraint: LOEUF 0.839 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 66.74

Full TRPM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPM1 p.Arg577Gln Uncertain significance ★ ⚠ same residue
TRPM1 c.1089+1G>A Likely pathogenic ★★ same type
TRPM1 c.2316+1G>A Pathogenic/Likely pathogenic ★★ same type
TRPM1 c.2317-1G>C Likely pathogenic ★★ same type
TRPM1 c.2440-2A>G Likely pathogenic ★★ same type
TRPM1 c.2571+1G>A Likely pathogenic ★★ same type
TRPM1 c.3127+1G>A Pathogenic/Likely pathogenic ★★ same type
TRPM1 c.3148+1G>A Pathogenic/Likely pathogenic ★★ 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/trpm1-p-arg577trp (accessed [today's date]).

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