Is TRPM4 p.Leu802Phe (c.2404C>T) pathogenic?

TRPM4 p.Leu802Phe (c.2404C>T) is classified Uncertain significance in TRPM4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-09). AlphaMissense: ambiguous (0.5607); Very rare (popmax 0.00704%, nfe); Associated with progressive familial heart block type IB.

What condition is associated with TRPM4 p.Leu802Phe (c.2404C>T)?

TRPM4 p.Leu802Phe (c.2404C>T) is associated with progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Leu802Phe (c.2404C>T) in the general population?

TRPM4 p.Leu802Phe (c.2404C>T) is very rare (popmax 0.00704%, nfe) (gnomAD).

What do computational predictors say about TRPM4 p.Leu802Phe (c.2404C>T)?

AlphaMissense predicts ambiguous (score 0.5607) — an in-silico prediction, not a clinical call.

TRPM4 p.Leu802Phe

Q: How is Hereditary progressive cardiac conduction defect inherited?

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

c.2404C>T · rs1289712382 · VCV451376

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5607 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00704%, nfe)

Conditions

progressive familial heart block type IB

Computational evidence

Protein change
AlphaMissense	0.5607	ambiguous
REVEL	0.529	indeterminate
SaProt	LLR -11.43	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 43 kb · p 0.93 · regional, not allelic
Overall
CADD	24.2	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 0.00704% European (non-Finnish) · 81/1,151,298 alleles

Filtering AF 0.00577% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00528%

Overall 0.00548% 85/1,551,306 alleles · very rare exomes 83/1,399,092 · genomes 2/152,214 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00704%	14,214
Remaining individualsnot grpmax-eligible	0.00332%	30,159
African / African-American	0.00136%	73,542
South Asian	0.00118%	84,658

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.Leu802Phe
Coding: c.2404C>T
MANE Select: NM_017636
dbSNP: rs1289712382
Type: single nucleotide variant
Location: chr19:49196633 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB
Residue 802: an α-helix

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.Leu802= 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
TRPM4 c.1263+2T>G 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-leu802phe (accessed [today's date]).

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