Is TRPM1 p.Pro421= (c.1263G>A) pathogenic?

TRPM1 p.Pro421= (c.1263G>A) is classified Conflicting classifications of pathogenicity in TRPM1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-07-05). Very rare (popmax 0.00446%, eas); Associated with TRPM1-related disorder.

What condition is associated with TRPM1 p.Pro421= (c.1263G>A)?

TRPM1 p.Pro421= (c.1263G>A) is associated with TRPM1-related disorder, night blindness, congenital stationary night blindness 1C (ClinVar).

How common is TRPM1 p.Pro421= (c.1263G>A) in the general population?

TRPM1 p.Pro421= (c.1263G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

TRPM1 p.Pro421=

c.1263G>A · rs768701595 · VCV225502

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

TRPM1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.46	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.33	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.2	GERP 2.7, phastCons 1
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000806% 13/1,613,684 alleles · very rare exomes 12/1,461,338 · genomes 1/152,346 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,442
Admixed American	0.00333%	30,012
European (non-Finnish)	0.000763%	131,065

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.Pro421=
Coding: c.1263G>A
MANE Select: NM_001252024
dbSNP: rs768701595
Type: single nucleotide variant
Location: chr15:31060544 (GRCh38)
Gene constraint: LOEUF 0.839 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 66.74
Residue 421: the 'disordered' region

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

Disease context

TRPM1-related disorder

Also linked: night blindness congenital stationary night blindness 1C congenital stationary night blindness

Similar variants

TRPM1 p.Pro421Thr Benign/Likely benign ★★ same residue
TRPM1 p.Pro421Leu Uncertain significance ★★ ⚠ same residue
TRPM1 c.1089+1G>A Likely pathogenic ★★ same condition
TRPM1 c.2316+1G>A Pathogenic/Likely pathogenic ★★ same condition
TRPM1 c.2317-1G>C Likely pathogenic ★★ same condition
TRPM1 c.2440-2A>G Likely pathogenic ★★ same condition
TRPM1 c.3127+1G>A Pathogenic/Likely pathogenic ★★ same condition
TRPM1 c.3148+1G>A 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-pro421 (accessed [today's date]).

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