Is TRPM4 p.Pro71Ser (c.211C>T) pathogenic?

TRPM4 p.Pro71Ser (c.211C>T) is classified Uncertain significance in TRPM4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-30). AlphaMissense: likely benign (0.3108); Very rare (popmax 0.00017%, nfe); Associated with progressive familial heart block type IB.

What condition is associated with TRPM4 p.Pro71Ser (c.211C>T)?

TRPM4 p.Pro71Ser (c.211C>T) is associated with progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Pro71Ser (c.211C>T) in the general population?

TRPM4 p.Pro71Ser (c.211C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about TRPM4 p.Pro71Ser (c.211C>T)?

AlphaMissense predicts likely benign (score 0.3108) — an in-silico prediction, not a clinical call.

TRPM4 p.Pro71Ser

Q: How is Hereditary progressive cardiac conduction defect inherited?

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

c.211C>T · rs773878985 · VCV2812408

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3108 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive familial heart block type IB

Computational evidence

Protein change
AlphaMissense	0.3108	likely benign
REVEL	0.694	pathogenic-leaning
SaProt	LLR -9.40	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.94 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,178,386 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000206% 3/1,456,398 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,244
European (non-Finnish)grpmax	0.00017%	589,192

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.Pro71Ser
Coding: c.211C>T
MANE Select: NM_017636
dbSNP: rs773878985
Type: single nucleotide variant
Location: chr19:49166159 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB
Residue 71: a β-strand

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.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-pro71ser (accessed [today's date]).

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