Is TRPM4 p.Phe207Ile (c.619T>A) pathogenic?

TRPM4 p.Phe207Ile (c.619T>A) is classified Uncertain significance in TRPM4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-15). AlphaMissense: ambiguous (0.366); Very rare (popmax 0.00267%, afr); Associated with Cardiovascular phenotype.

What condition is associated with TRPM4 p.Phe207Ile (c.619T>A)?

TRPM4 p.Phe207Ile (c.619T>A) is associated with Cardiovascular phenotype, progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Phe207Ile (c.619T>A) in the general population?

TRPM4 p.Phe207Ile (c.619T>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TRPM4 p.Phe207Ile (c.619T>A)?

AlphaMissense predicts ambiguous (score 0.366) — an in-silico prediction, not a clinical call.

TRPM4 p.Phe207Ile

c.619T>A · VCV3667692

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.366 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.366	ambiguous
REVEL	0.253	benign-leaning
SaProt	LLR -4.50	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
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 · 43 kb · p 0.93 · regional, not allelic
Overall
CADD	22.8	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 0.00267% African / African-American · 2/74,900 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,686 alleles · very rare exomes 2/1,461,634 · genomes 1/152,052 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,450
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Phe207Ile
Coding: c.619T>A
MANE Select: NM_017636
Type: single nucleotide variant
Location: chr19:49168559 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB
Residue 207: a β-strand

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-phe207ile (accessed [today's date]).

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