Is TRPM4 p.Pro4Ser (c.10C>T) pathogenic?

TRPM4 p.Pro4Ser (c.10C>T) is classified Conflicting classifications of pathogenicity in TRPM4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-15). AlphaMissense: likely benign (0.07); Very rare (popmax 8.72e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with TRPM4 p.Pro4Ser (c.10C>T)?

TRPM4 p.Pro4Ser (c.10C>T) is associated with Cardiovascular phenotype, progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Pro4Ser (c.10C>T) in the general population?

TRPM4 p.Pro4Ser (c.10C>T) is very rare (popmax 8.72e-05%, nfe) (gnomAD).

What do computational predictors say about TRPM4 p.Pro4Ser (c.10C>T)?

AlphaMissense predicts likely benign (score 0.07) — an in-silico prediction, not a clinical call.

TRPM4 p.Pro4Ser

c.10C>T · rs1280227892 · VCV1525658

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.07 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.72e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.07	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -6.20	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 -3.1
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.94 · regional, not allelic
Overall
CADD	1.991	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 8.72e-05% European (non-Finnish) · 1/1,146,410 alleles

Overall 7.23e-05% 1/1,382,618 alleles · very rare

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.Pro4Ser
Coding: c.10C>T
MANE Select: NM_017636
dbSNP: rs1280227892
Type: single nucleotide variant
Location: chr19:49157876 (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

Also linked: progressive familial heart block type IB

Similar variants

TRPM4 p.Pro4Arg Uncertain significance ★★ ⚠ same residue
TRPM4 p.Pro4= Likely benign ★ same residue
TRPM4 p.Ile1040Thr Pathogenic/Likely pathogenic ★★ same condition
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.1150+6A>G Uncertain significance ★★ same condition
TRPM4 c.1263+1G>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-pro4ser (accessed [today's date]).

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