Is TRPM4 p.Lys261= (c.783G>A) pathogenic?

TRPM4 p.Lys261= (c.783G>A) is classified Benign/Likely benign in TRPM4 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-03). Low-frequency (popmax 3.51%, sas); Associated with Cardiovascular phenotype.

What condition is associated with TRPM4 p.Lys261= (c.783G>A)?

TRPM4 p.Lys261= (c.783G>A) is associated with Cardiovascular phenotype, progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Lys261= (c.783G>A) in the general population?

TRPM4 p.Lys261= (c.783G>A) is low-frequency (popmax 3.51%, sas) (gnomAD).

TRPM4 p.Lys261=

c.783G>A · rs111930830 · VCV220961

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.51%, sas)

Conditions

Cardiovascular phenotype

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 9.4	phastCons 1
Overall
CADD	11.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.51% South Asian · 3,096/88,130 alleles

Filtering AF 3.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.37%

Overall 1.71% 27,231/1,591,836 alleles · low-frequency exomes 24,405/1,439,742 · genomes 2,826/152,094 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	3.51%	28
Finnishnot grpmax-eligible	3.47%	29
Ashkenazi Jewishnot grpmax-eligible	3.04%	33
Middle Eastern	1.64%	61
Remaining individualsnot grpmax-eligible	1.6%	62
European (non-Finnish)	1.59%	63
African / African-American	1.42%	70
Admixed American	0.696%	144
East Asian	0.0137%	7,317

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.Lys261=
Coding: c.783G>A
MANE Select: NM_017636
dbSNP: rs111930830
Type: single nucleotide variant
Location: chr19:49168723 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB
Residue 261: a β-strand

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.Lys261Glu 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-lys261 (accessed [today's date]).

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