Is TRPM4 p.Ala83= (c.249C>G) pathogenic?

TRPM4 p.Ala83= (c.249C>G) is classified Likely benign in TRPM4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-17). Very rare (popmax 0.00289%, nfe); Associated with progressive familial heart block type IB.

What condition is associated with TRPM4 p.Ala83= (c.249C>G)?

TRPM4 p.Ala83= (c.249C>G) is associated with progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Ala83= (c.249C>G) in the general population?

TRPM4 p.Ala83= (c.249C>G) is very rare (popmax 0.00289%, nfe) (gnomAD).

TRPM4 p.Ala83=

Q: How is Hereditary progressive cardiac conduction defect inherited?

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

c.249C>G · rs142270489 · VCV1602529

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00289%, nfe)

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 -3.9
Overall
CADD	0.515	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00289% European (non-Finnish) · 34/1,177,388 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.0023% 37/1,606,096 alleles · very rare exomes 36/1,453,976 · genomes 1/152,120 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00289%	34,629
Admixed American	0.0017%	58,926
Remaining individualsnot grpmax-eligible	0.00161%	62,078
African / African-American	0.00134%	74,818

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.Ala83=
Coding: c.249C>G
MANE Select: NM_017636
dbSNP: rs142270489
Type: single nucleotide variant
Location: chr19:49166197 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB
Residue 83: a β-strand

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.Ala83Gly Uncertain significance ★★ ⚠ same residue
TRPM4 p.Ala83Ser Uncertain significance ★★ ⚠ same residue
TRPM4 p.Ala83fs Uncertain significance ★★ same residue
TRPM4 p.Ala83Val 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

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-ala83 (accessed [today's date]).

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