Is TRPM8 p.Phe165Ser (c.494T>C) pathogenic?

TRPM8 p.Phe165Ser (c.494T>C) is classified Uncertain significance in TRPM8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-22). AlphaMissense: likely pathogenic (0.8195); Very rare (popmax 0.00167%, amr).

How common is TRPM8 p.Phe165Ser (c.494T>C) in the general population?

TRPM8 p.Phe165Ser (c.494T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TRPM8 p.Phe165Ser (c.494T>C)?

AlphaMissense predicts likely pathogenic (score 0.8195) — an in-silico prediction, not a clinical call.

TRPM8 p.Phe165Ser

c.494T>C · rs201611229 · VCV3183437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8195 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8195	likely pathogenic
REVEL	0.552	indeterminate
SaProt	LLR -10.37	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 7.6	GERP 8.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 44 kb · p 0.85 · regional, not allelic
Overall
CADD	25.6	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,032 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,614,126 alleles · very rare exomes 9/1,461,786 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,032
European (non-Finnish)	0.000678%	147,505

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: TRPM8
Protein: p.Phe165Ser
Coding: c.494T>C
MANE Select: NM_024080
dbSNP: rs201611229
Type: single nucleotide variant
Location: chr2:233939143 (GRCh38)
Gene constraint: LOEUF 0.945 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.42 · 6 PDB
Residue 165: an α-helix

Full TRPM8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPM8 p.Phe165Cys Uncertain significance ★ same residue
TRPM8 p.Arg247Thr Benign ★★ same type
TRPM8 p.Asn821Ser Benign ★★ same type
TRPM8 p.Glu545= Benign ★★ same type
TRPM8 p.Leu226= Benign ★★ same type
TRPM8 p.Met462Thr Benign ★★ ⚠ same type
TRPM8 p.Pro916= Benign ★★ same type
TRPM8 p.Ala1071Pro Uncertain significance ★ ⚠ 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/trpm8-p-phe165ser (accessed [today's date]).

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