Is TRPM4 p.Ser471Pro (c.1411T>C) pathogenic?

TRPM4 p.Ser471Pro (c.1411T>C) is classified Uncertain significance in TRPM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-10). AlphaMissense: likely pathogenic (0.6734); Very rare (popmax 0.00133%, afr); Associated with Cardiovascular phenotype.

What condition is associated with TRPM4 p.Ser471Pro (c.1411T>C)?

TRPM4 p.Ser471Pro (c.1411T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is TRPM4 p.Ser471Pro (c.1411T>C) in the general population?

TRPM4 p.Ser471Pro (c.1411T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TRPM4 p.Ser471Pro (c.1411T>C)?

AlphaMissense predicts likely pathogenic (score 0.6734) — an in-silico prediction, not a clinical call.

TRPM4 p.Ser471Pro

c.1411T>C · VCV4841822

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6734 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.6734	likely pathogenic
REVEL	0.238	benign-leaning
SaProt	LLR -15.90	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 43 kb · p 0.93 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,038 alleles

Overall 6.2e-05% 1/1,613,980 alleles · very rare exomes 1/1,461,790 · genomes 0/152,190 · 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: TRPM4
Protein: p.Ser471Pro
Coding: c.1411T>C
MANE Select: NM_017636
Type: single nucleotide variant
Location: chr19:49182725 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB

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.Ser471Leu Uncertain significance ★★ ⚠ 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-ser471pro (accessed [today's date]).

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