Is TRPM4 p.Pro115fs (c.344del) pathogenic?

TRPM4 p.Pro115fs (c.344del) is classified Uncertain significance in TRPM4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-11). Very rare (popmax 0.000339%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with TRPM4 p.Pro115fs (c.344del)?

TRPM4 p.Pro115fs (c.344del) is associated with Cardiovascular phenotype, progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Pro115fs (c.344del) in the general population?

TRPM4 p.Pro115fs (c.344del) is very rare (popmax 0.000339%, nfe) (gnomAD).

TRPM4 p.Pro115fs

c.344del · rs777609699 · VCV632316

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.2	phastCons 1
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,030 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,890 alleles · very rare

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.Pro115fs
Coding: c.344del
MANE Select: NM_017636
dbSNP: rs777609699
Type: Deletion
Location: chr19:49167990 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB
Residue 115: an α-helix

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.Pro115Leu Uncertain significance ★★ ⚠ same residue
TRPM4 p.Pro115= Likely benign ★★ same residue
TRPM4 p.Pro115Ser Uncertain significance ★ ⚠ same residue
TRPM4 p.Ala1006fs Uncertain significance ★★ same condition
TRPM4 p.Ala665fs Uncertain significance ★★ same condition
TRPM4 p.Ala83fs Uncertain significance ★★ same condition
TRPM4 p.Arg499_Asp502del Uncertain significance ★★ same condition
TRPM4 p.Asp417fs 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-pro115fs (accessed [today's date]).

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