Is TRPM1 p.Ala45Pro (c.133G>C) pathogenic?

TRPM1 p.Ala45Pro (c.133G>C) is classified Uncertain significance in TRPM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely benign (0.1012); Ultra-rare (popmax 0.0494%, sas); Associated with Inborn genetic diseases.

What condition is associated with TRPM1 p.Ala45Pro (c.133G>C)?

TRPM1 p.Ala45Pro (c.133G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TRPM1 p.Ala45Pro (c.133G>C) in the general population?

TRPM1 p.Ala45Pro (c.133G>C) is ultra-rare (popmax 0.0494%, sas) (gnomAD).

What do computational predictors say about TRPM1 p.Ala45Pro (c.133G>C)?

AlphaMissense predicts likely benign (score 0.1012) — an in-silico prediction, not a clinical call.

TRPM1 p.Ala45Pro

c.133G>C · rs776269372 · VCV3183271

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1012 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1012	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -5.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.98	GERP -5.4
Regional constraint	o/e 0.99	unconstrained · MANE · 53 kb · p 0.68 · regional, not allelic
Overall
CADD	1.338	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 A23P vs ClinVar A45P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0494% South Asian · 45/91,082 alleles

Filtering AF 0.0379% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0339%

Overall 0.00285% 46/1,613,958 alleles · ultra-rare exomes 45/1,461,790 · genomes 1/152,168 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0494%	2,024
European (non-Finnish)	8.47e-05%	1,179,990

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.Ala45Pro
Coding: c.133G>C
MANE Select: NM_001252024
dbSNP: rs776269372
Type: single nucleotide variant
Location: chr15:31070177 (GRCh38)
Gene constraint: LOEUF 0.839 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 66.74
Residue 23 UniProt numbering: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRPM1 p.Ala45Thr Uncertain significance ★ ⚠ same residue
TRPM1 p.Ala45Val Uncertain significance ★ ⚠ same residue
TRPM1 p.Ala1240Pro Uncertain significance ★★ ⚠ same condition
TRPM1 p.Ala1364Val Uncertain significance ★★ ⚠ same condition
TRPM1 p.Ala1371Pro Uncertain significance ★★ ⚠ same condition
TRPM1 p.Ala1453Asp Uncertain significance ★★ ⚠ same condition
TRPM1 p.Ala150Ser Uncertain significance ★★ ⚠ same condition
TRPM1 p.Ala1534Thr Uncertain significance ★★ ⚠ 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/trpm1-p-ala45pro (accessed [today's date]).

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