Is TRPC4 p.Val718Ile (c.2152G>A) pathogenic?

TRPC4 p.Val718Ile (c.2152G>A) is classified Uncertain significance in TRPC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-11). AlphaMissense: likely benign (0.2287); Very rare (popmax 0.005%, amr).

How common is TRPC4 p.Val718Ile (c.2152G>A) in the general population?

TRPC4 p.Val718Ile (c.2152G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about TRPC4 p.Val718Ile (c.2152G>A)?

AlphaMissense predicts likely benign (score 0.2287) — an in-silico prediction, not a clinical call.

TRPC4 p.Val718Ile

c.2152G>A · rs377547600 · VCV2364303

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2287 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2287	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -7.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 14 kb · p 0.77 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,980 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00167% 27/1,613,538 alleles · very rare exomes 25/1,461,424 · genomes 2/152,114 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,993
East Asian	0.00223%	44,872
South Asian	0.0022%	45,540
European (non-Finnish)	0.00161%	62,087
Remaining individualsnot grpmax-eligible	0.0016%	62,470
African / African-American	0.00134%	74,886

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.Val718Ile
Coding: c.2152G>A
MANE Select: NM_016179
dbSNP: rs377547600
Type: single nucleotide variant
Location: chr13:37639099 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.71 · 3 PDB
Residue 718: the 'interaction with itpr1, itpr2 and itpr3' region; an α-helix

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-val718ile (accessed [today's date]).

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