Is TRPM4 p.Val3Ala (c.8T>C) pathogenic?

TRPM4 p.Val3Ala (c.8T>C) is classified Uncertain significance in TRPM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-12). AlphaMissense: likely benign (0.0795); Ultra-rare (popmax 0.0192%, mid); Associated with progressive familial heart block type IB.

What condition is associated with TRPM4 p.Val3Ala (c.8T>C)?

TRPM4 p.Val3Ala (c.8T>C) is associated with progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Val3Ala (c.8T>C) in the general population?

TRPM4 p.Val3Ala (c.8T>C) is ultra-rare (popmax 0.0192%, mid) (gnomAD).

What do computational predictors say about TRPM4 p.Val3Ala (c.8T>C)?

AlphaMissense predicts likely benign (score 0.0795) — an in-silico prediction, not a clinical call.

TRPM4 p.Val3Ala

Q: How is Hereditary progressive cardiac conduction defect inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.8T>C · rs1600378229 · VCV1447130

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0795 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0192%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive familial heart block type IB

Computational evidence

Protein change
AlphaMissense	0.0795	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -5.91	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 0.77	phastCons 0.038
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.94 · regional, not allelic
Overall
CADD	6.235	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0192% Middle Eastern · 1/5,214 alleles

Overall 0.000289% 4/1,382,460 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0192%	5,214
Remaining individualsnot grpmax-eligible	0.00167%	59,896
South Asian	0.00119%	83,946
European (non-Finnish)	8.72e-05%	1,146,354

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.Val3Ala
Coding: c.8T>C
MANE Select: NM_017636
dbSNP: rs1600378229
Type: single nucleotide variant
Location: chr19:49157874 (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

progressive familial heart block type IB — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary progressive cardiac conduction defect (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

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
TRPM4 c.1263+2T>G Uncertain significance ★★ same condition
TRPM4 c.1608+1G>C 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-val3ala (accessed [today's date]).

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