Is TRPM4 p.Pro520fs (c.1559_1560del) pathogenic?

TRPM4 p.Pro520fs (c.15591560del) is classified Uncertain significance in TRPM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-27). Very rare (popmax 0.00221%, sas); Associated with progressive familial heart block type IB.

What condition is associated with TRPM4 p.Pro520fs (c.1559_1560del)?

TRPM4 p.Pro520fs (c.1559_1560del) is associated with progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Pro520fs (c.1559_1560del) in the general population?

TRPM4 p.Pro520fs (c.1559_1560del) is very rare (popmax 0.00221%, sas) (gnomAD).

TRPM4 p.Pro520fs

Q: How is Hereditary progressive cardiac conduction defect inherited?

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

c.1559_1560del · rs1413934947 · VCV1466352

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00221%, sas)

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 1.7	phastCons 0.99

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00221% South Asian · 2/90,628 alleles

Filtering AF 0.000366% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000137% 2/1,455,776 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.Pro520fs
Coding: c.1559_1560del
MANE Select: NM_017636
dbSNP: rs1413934947
Type: Deletion
Location: chr19:49182871 (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

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 p.Pro520Arg 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
TRPM4 p.Gly127fs Uncertain significance ★★ same condition
TRPM4 p.Gly838fs 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-pro520fs (accessed [today's date]).

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