Is TRPM1 p.Ser888Phe (c.2663C>T) pathogenic?

TRPM1 p.Ser888Phe (c.2663C>T) is classified Uncertain significance in TRPM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.243); Very rare (popmax 0.00549%, sas); Associated with Inborn genetic diseases.

What condition is associated with TRPM1 p.Ser888Phe (c.2663C>T)?

TRPM1 p.Ser888Phe (c.2663C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TRPM1 p.Ser888Phe (c.2663C>T) in the general population?

TRPM1 p.Ser888Phe (c.2663C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about TRPM1 p.Ser888Phe (c.2663C>T)?

AlphaMissense predicts likely benign (score 0.243) — an in-silico prediction, not a clinical call.

TRPM1 p.Ser888Phe

c.2663C>T · VCV4191651

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.243 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.243	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 53 kb · p 0.68 · regional, not allelic
Overall
CADD	24.2	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 S866F vs ClinVar S888F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,090 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000434% 7/1,613,946 alleles · very rare exomes 5/1,461,730 · genomes 2/152,216 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,218
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	8.48e-05%	1,179,885

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.Ser888Phe
Coding: c.2663C>T
MANE Select: NM_001252024
Type: single nucleotide variant
Location: chr15:31035583 (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

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

Similar variants

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
TRPM1 p.Arg1063Trp Uncertain significance ★★ ⚠ same condition
TRPM1 p.Arg1268Gln 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-ser888phe (accessed [today's date]).

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