Is TRPC4 p.Arg288Lys (c.863G>A) pathogenic?

TRPC4 p.Arg288Lys (c.863G>A) is classified Uncertain significance in TRPC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely pathogenic (0.8698); Absent from gnomAD v4.1.

How common is TRPC4 p.Arg288Lys (c.863G>A) in the general population?

TRPC4 p.Arg288Lys (c.863G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TRPC4 p.Arg288Lys (c.863G>A)?

AlphaMissense predicts likely pathogenic (score 0.8698) — an in-silico prediction, not a clinical call.

TRPC4 p.Arg288Lys

c.863G>A · VCV3974134

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8698 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8698	likely pathogenic
REVEL	0.313	indeterminate
SaProt	LLR -9.49	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 37 kb · p 0.00023 · regional, not allelic
Overall
CADD	22.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TRPC4
Protein: p.Arg288Lys
Coding: c.863G>A
MANE Select: NM_016179
Type: single nucleotide variant
Location: chr13:37745971 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.71 · 3 PDB
Residue 288: 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-arg288lys (accessed [today's date]).

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