Is TRPM4 p.Val506= (c.1518G>C) pathogenic?

TRPM4 p.Val506= (c.1518G>C) is classified Likely benign in TRPM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). Absent from gnomAD v4.1; Associated with progressive familial heart block type IB.

What condition is associated with TRPM4 p.Val506= (c.1518G>C)?

TRPM4 p.Val506= (c.1518G>C) is associated with progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Val506= (c.1518G>C) in the general population?

TRPM4 p.Val506= (c.1518G>C) is absent from gnomAD v4.1 (gnomAD).

TRPM4 p.Val506=

Q: How is Hereditary progressive cardiac conduction defect inherited?

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

c.1518G>C · rs2514116660 · VCV1996710

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 1.9	phastCons 1
Overall
CADD	6.266	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TRPM4
Protein: p.Val506=
Coding: c.1518G>C
MANE Select: NM_017636
dbSNP: rs2514116660
Type: single nucleotide variant
Location: chr19:49182832 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB
Residue 506: 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.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-val506 (accessed [today's date]).

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