Is TRPM4 p.Pro438fs (c.1311dup) pathogenic?

TRPM4 p.Pro438fs (c.1311dup) is classified Uncertain significance in TRPM4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-23). Very rare (popmax 0.00169%, nfe); Associated with progressive familial heart block type IB.

What condition is associated with TRPM4 p.Pro438fs (c.1311dup)?

TRPM4 p.Pro438fs (c.1311dup) is associated with progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Pro438fs (c.1311dup) in the general population?

TRPM4 p.Pro438fs (c.1311dup) is very rare (popmax 0.00169%, nfe) (gnomAD).

TRPM4 p.Pro438fs

Q: How is Hereditary progressive cardiac conduction defect inherited?

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

c.1311dup · rs755946769 · VCV518808

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00169%, 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.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.3	phastCons 1
Overall
CADD	29.1	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 0.00169% European (non-Finnish) · 20/1,180,050 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00136% 22/1,614,026 alleles · very rare exomes 18/1,461,782 · genomes 4/152,244 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)grpmax	0.00169%	59,003

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro438fs
Coding: c.1311dup
MANE Select: NM_017636
dbSNP: rs755946769
Type: Duplication
Location: chr19:49182623 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB
Residue 438: an α-helix

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 c.1606_1608+1dup Uncertain significance ★★ same condition
TRPM4 p.Arg766fs Uncertain significance ★★ same condition
TRPM4 p.Cys1011fs Uncertain significance ★★ same condition
TRPM4 p.Leu1209Ter Uncertain significance ★★ same condition
TRPM4 p.Ser125fs Uncertain significance ★★ same condition
TRPM4 p.Ser839fs Uncertain significance ★★ same condition
TRPM4 c.1050+13_1050+16dup Benign ★★ same condition
TRPM4 c.796+30_796+43dup 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-pro438fs (accessed [today's date]).

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