Is TRPM1 p.Leu129Pro (c.386T>C) pathogenic?

TRPM1 p.Leu129Pro (c.386T>C) is classified Uncertain significance in TRPM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-27). AlphaMissense: likely pathogenic (0.8379); Very rare (popmax 0.000169%, nfe); Associated with congenital stationary night blindness 1C.

What condition is associated with TRPM1 p.Leu129Pro (c.386T>C)?

TRPM1 p.Leu129Pro (c.386T>C) is associated with congenital stationary night blindness 1C (ClinVar).

How common is TRPM1 p.Leu129Pro (c.386T>C) in the general population?

TRPM1 p.Leu129Pro (c.386T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about TRPM1 p.Leu129Pro (c.386T>C)?

AlphaMissense predicts likely pathogenic (score 0.8379) — an in-silico prediction, not a clinical call.

TRPM1 p.Leu129Pro

c.386T>C · rs2034428006 · VCV887453

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8379 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

congenital stationary night blindness 1C

Computational evidence

Protein change
AlphaMissense	0.8379	likely pathogenic
REVEL	0.556	indeterminate
SaProt	LLR -12.64	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 53 kb · p 0.68 · regional, not allelic
Overall
CADD	29.0	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 L107P vs ClinVar L129P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,046 alleles

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

Overall 0.000124% 2/1,614,060 alleles · very rare exomes 0/1,461,888 · genomes 2/152,172 · 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.Leu129Pro
Coding: c.386T>C
MANE Select: NM_001252024
dbSNP: rs2034428006
Type: single nucleotide variant
Location: chr15:31067986 (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

Disease context

congenital stationary night blindness 1C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRPM1 p.Leu129= Likely benign ★ same residue
TRPM1 c.1089+1G>A Likely pathogenic ★★ same condition
TRPM1 c.3127+1G>A Pathogenic/Likely pathogenic ★★ same condition
TRPM1 c.3148+1G>A Pathogenic/Likely pathogenic ★★ same condition
TRPM1 c.83+1G>A Likely pathogenic ★★ same condition
TRPM1 p.Ala848Val Pathogenic/Likely pathogenic ★★ same condition
TRPM1 p.Arg646Cys Pathogenic/Likely pathogenic ★★ same condition
TRPM1 p.Arg656Ter 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/trpm1-p-leu129pro (accessed [today's date]).

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