Is TRPC4 p.Ile18Val (c.52A>G) pathogenic?

TRPC4 p.Ile18Val (c.52A>G) is classified Uncertain significance in TRPC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely pathogenic (0.6936); Very rare (popmax 0.000254%, nfe).

How common is TRPC4 p.Ile18Val (c.52A>G) in the general population?

TRPC4 p.Ile18Val (c.52A>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about TRPC4 p.Ile18Val (c.52A>G)?

AlphaMissense predicts likely pathogenic (score 0.6936) — an in-silico prediction, not a clinical call.

TRPC4 p.Ile18Val

c.52A>G · VCV4599581

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6936	likely pathogenic
REVEL	0.194	benign-leaning
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 37 kb · p 0.00023 · regional, not allelic
Overall
CADD	24.6	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 0.000254% European (non-Finnish) · 3/1,179,384 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,612,698 alleles · very rare exomes 3/1,460,434 · genomes 0/152,264 · joint denominator

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: TRPC4
Protein: p.Ile18Val
Coding: c.52A>G
MANE Select: NM_016179
Type: single nucleotide variant
Location: chr13:37783282 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.71 · 3 PDB
Residue 18: a β-strand

Full TRPC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPC4 p.Arg976= Benign ★★ same type
TRPC4 p.Cys333= Benign ★★ same type
TRPC4 c.379-2A>T Pathogenic ★ same type
TRPC4 p.Ala327Val Uncertain significance ★ ⚠ same type
TRPC4 p.Ala484Thr Uncertain significance ★ ⚠ same type
TRPC4 p.Ala697Thr Uncertain significance ★ same type
TRPC4 p.Ala720Glu Uncertain significance ★ ⚠ same type
TRPC4 p.Ala808Thr Uncertain significance ★ ⚠ same type

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/trpc4-p-ile18val (accessed [today's date]).

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