Is TRPM1 p.Trp1492Arg (c.4474T>C) pathogenic?

TRPM1 p.Trp1492Arg (c.4474T>C) is classified Uncertain significance in TRPM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-24). AlphaMissense: ambiguous (0.3883); Very rare (popmax 0.000169%, nfe).

How common is TRPM1 p.Trp1492Arg (c.4474T>C) in the general population?

TRPM1 p.Trp1492Arg (c.4474T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about TRPM1 p.Trp1492Arg (c.4474T>C)?

AlphaMissense predicts ambiguous (score 0.3883) — an in-silico prediction, not a clinical call.

TRPM1 p.Trp1492Arg

c.4474T>C · rs2141099058 · VCV1369029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3883 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3883	ambiguous
REVEL	0.224	benign-leaning
SaProt	LLR -3.49	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP -0.009, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 25 kb · p 0.77 · regional, not allelic
Overall
CADD	21.9	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 W1470R vs ClinVar W1492R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,042 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,252 alleles · very rare exomes 2/1,461,894 · genomes 0/152,358 · 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: TRPM1
Protein: p.Trp1492Arg
Coding: c.4474T>C
MANE Select: NM_001252024
dbSNP: rs2141099058
Type: single nucleotide variant
Location: chr15:31002226 (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.Trp1492Ter Conflicting classifications of pathogenicity ★ 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-trp1492arg (accessed [today's date]).

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