Is TRPM4 p.Ala496= (c.1488G>A) pathogenic?

TRPM4 p.Ala496= (c.1488G>A) is classified Likely benign in TRPM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-02-12). Very rare (popmax 0.00445%, sas); Associated with progressive familial heart block type IB.

What condition is associated with TRPM4 p.Ala496= (c.1488G>A)?

TRPM4 p.Ala496= (c.1488G>A) is associated with progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Ala496= (c.1488G>A) in the general population?

TRPM4 p.Ala496= (c.1488G>A) is very rare (popmax 0.00445%, sas) (gnomAD).

TRPM4 p.Ala496=

Q: How is Hereditary progressive cardiac conduction defect inherited?

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

c.1488G>A · rs1371428909 · VCV742688

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00445%, sas)

Conditions

progressive familial heart block type IB

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8
Overall
CADD	0.856	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% South Asian · 4/89,856 alleles

Filtering AF 0.00144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00035% 5/1,427,410 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00445%	22,464
Remaining individualsnot grpmax-eligible	0.00164%	61,112

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.Ala496=
Coding: c.1488G>A
MANE Select: NM_017636
dbSNP: rs1371428909
Type: single nucleotide variant
Location: chr19:49182802 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB
Residue 496: a UniProt-annotated variant site (sequence variant)

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.Ala496Gly Uncertain significance ★★ ⚠ same residue
TRPM4 p.Ala496Thr Uncertain significance ★ ⚠ same residue
TRPM4 p.Ala496Val Uncertain significance ★ ⚠ 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

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-ala496 (accessed [today's date]).

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