Is TRPM4 p.Ser994= (c.2982G>A) pathogenic?

TRPM4 p.Ser994= (c.2982G>A) is classified Benign in TRPM4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-03). Common (popmax 9.56%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with TRPM4 p.Ser994= (c.2982G>A)?

TRPM4 p.Ser994= (c.2982G>A) is associated with Cardiovascular phenotype, progressive familial heart block type IB (ClinVar).

TRPM4 p.Ser994=

Q: How common is TRPM4 p.Ser994= (c.2982G>A) in the general population?

TRPM4 p.Ser994= (c.2982G>A) is common (popmax 9.56%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2982G>A · rs1175810 · VCV329870

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 9.56%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -6
Overall
CADD	0.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.56% African / African-American · 7,175/75,016 alleles

Filtering AF 9.38% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.3%

Overall 0.533% 8,607/1,613,742 alleles · common exomes 4,344/1,461,484 · genomes 4,263/152,258 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.56%	10
Admixed American	0.895%	112
Remaining individualsnot grpmax-eligible	0.842%	119
Middle Eastern	0.577%	173
South Asian	0.116%	859
European (non-Finnish)	0.019%	5,268
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
East Asian	0.00223%	44,870

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.Ser994=
Coding: c.2982G>A
MANE Select: NM_017636
dbSNP: rs1175810
Type: single nucleotide variant
Location: chr19:49201992 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: progressive familial heart block type IB

Similar variants

TRPM4 p.Ser994Leu 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
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-ser994 (accessed [today's date]).

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