Is TRPM4 p.Leu596Pro (c.1787T>C) pathogenic?

TRPM4 p.Leu596Pro (c.1787T>C) is classified Uncertain significance in TRPM4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-03). AlphaMissense: likely pathogenic (0.9531); Very rare (popmax 0.00401%, afr); Associated with hypertrophic cardiomyopathy.

What condition is associated with TRPM4 p.Leu596Pro (c.1787T>C)?

TRPM4 p.Leu596Pro (c.1787T>C) is associated with hypertrophic cardiomyopathy, progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Leu596Pro (c.1787T>C) in the general population?

TRPM4 p.Leu596Pro (c.1787T>C) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about TRPM4 p.Leu596Pro (c.1787T>C)?

AlphaMissense predicts likely pathogenic (score 0.9531) — an in-silico prediction, not a clinical call.

TRPM4 p.Leu596Pro

c.1787T>C · rs946021556 · VCV691672

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9531 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.9531	likely pathogenic · top 5% in TRPM4
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -14.65	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 7.6	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 43 kb · p 0.93 · regional, not allelic
Overall
CADD	25.8	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 0.00401% African / African-American · 3/74,884 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,613,986 alleles · very rare exomes 1/1,461,892 · genomes 3/152,094 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,961
Admixed American	0.00167%	59,992

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.Leu596Pro
Coding: c.1787T>C
MANE Select: NM_017636
dbSNP: rs946021556
Type: single nucleotide variant
Location: chr19:49188684 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB
Residue 596: an α-helix

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

Disease context

hypertrophic cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: progressive familial heart block type IB

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-leu596pro (accessed [today's date]).

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