Is TRPM4 p.Phe627Ser (c.1880T>C) pathogenic?

TRPM4 p.Phe627Ser (c.1880T>C) is classified Uncertain significance in TRPM4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-20). AlphaMissense: likely pathogenic (0.9187); Very rare (popmax 0.00333%, amr); Associated with Cardiovascular phenotype.

What condition is associated with TRPM4 p.Phe627Ser (c.1880T>C)?

TRPM4 p.Phe627Ser (c.1880T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is TRPM4 p.Phe627Ser (c.1880T>C) in the general population?

TRPM4 p.Phe627Ser (c.1880T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about TRPM4 p.Phe627Ser (c.1880T>C)?

AlphaMissense predicts likely pathogenic (score 0.9187) — an in-silico prediction, not a clinical call.

TRPM4 p.Phe627Ser

c.1880T>C · rs991572485 · VCV1723766

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9187	likely pathogenic · top 9% in TRPM4
REVEL	0.645	pathogenic-leaning
SaProt	LLR -11.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 43 kb · p 0.93 · regional, not allelic
Overall
CADD	22.4	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 0.00333% Admixed American · 2/60,012 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000205% 3/1,461,814 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,006
South Asian	0.0011%	91,086

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: TRPM4
Protein: p.Phe627Ser
Coding: c.1880T>C
MANE Select: NM_017636
dbSNP: rs991572485
Type: single nucleotide variant
Location: chr19:49188952 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB
Residue 627: an α-helix

Full TRPM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRPM4 p.Phe627= Likely benign ★★ same residue
TRPM4 p.Ile376Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
TRPM4 c.1050+1G>A Uncertain significance ★★ same condition
TRPM4 c.1150+5A>T Uncertain significance ★★ same condition
TRPM4 c.2019+5G>A Uncertain significance ★★ same condition
TRPM4 c.2645+1G>A Uncertain significance ★★ same condition
TRPM4 c.2953+1G>A Uncertain significance ★★ same condition
TRPM4 c.2953+5G>A 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/trpm4-p-phe627ser (accessed [today's date]).

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