Is TRPM4 p.Phe414= (c.1242T>C) pathogenic?

TRPM4 p.Phe414= (c.1242T>C) is classified Conflicting classifications of pathogenicity in TRPM4 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-12-19). Ultra-rare (popmax 0.019%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with TRPM4 p.Phe414= (c.1242T>C)?

TRPM4 p.Phe414= (c.1242T>C) is associated with Cardiovascular phenotype, progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Phe414= (c.1242T>C) in the general population?

TRPM4 p.Phe414= (c.1242T>C) is ultra-rare (popmax 0.019%, nfe) (gnomAD).

TRPM4 p.Phe414=

c.1242T>C · rs200633475 · VCV329854

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.019%, nfe)

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 3.2	phastCons 1
Overall
CADD	13.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.019% European (non-Finnish) · 224/1,179,860 alleles

Filtering AF 0.0169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0162%

Overall 0.0149% 240/1,613,218 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.019%	5,267
Remaining individualsnot grpmax-eligible	0.0144%	6,941
Finnishnot grpmax-eligible	0.00627%	15,937
Admixed American	0.00334%	29,967
African / African-American	0.00134%	74,702

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.Phe414=
Coding: c.1242T>C
MANE Select: NM_017636
dbSNP: rs200633475
Type: single nucleotide variant
Location: chr19:49181440 (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.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-phe414 (accessed [today's date]).

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