Is TRPC5 p.Val233Met (c.697G>A) pathogenic?

TRPC5 p.Val233Met (c.697G>A) is classified Uncertain significance in TRPC5 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-05-05). AlphaMissense: ambiguous (0.4326); Ultra-rare (popmax 0.0268%, nfe).

How common is TRPC5 p.Val233Met (c.697G>A) in the general population?

TRPC5 p.Val233Met (c.697G>A) is ultra-rare (popmax 0.0268%, nfe) (gnomAD).

What do computational predictors say about TRPC5 p.Val233Met (c.697G>A)?

AlphaMissense predicts ambiguous (score 0.4326) — an in-silico prediction, not a clinical call.

TRPC5 p.Val233Met

c.697G>A · rs145338486 · VCV2242542

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4326 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4326	ambiguous
REVEL	0.288	benign-leaning
SaProt	LLR -6.57	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 6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 131 kb · p 1e-26 · regional, not allelic
Overall
CADD	25.2	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 0.0268% European (non-Finnish) · 240/895,229 alleles

Filtering AF 0.024% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0228%

Overall 0.0201% 243/1,209,724 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0268%	3,730
Remaining individualsnot grpmax-eligible	0.00631%	15,859

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: TRPC5
Protein: p.Val233Met
Coding: c.697G>A
MANE Select: NM_012471
dbSNP: rs145338486
Type: single nucleotide variant
Location: chrX:111912494 (GRCh38)
Structure: AlphaFold pLDDT 73.82 · 30 PDB
Residue 233: an α-helix

Full TRPC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPC5 p.Ala929Thr Uncertain significance ★ ⚠ same type
TRPC5 p.Arg120Gln Uncertain significance ★ ⚠ same type
TRPC5 p.Arg175Cys Uncertain significance ★ ⚠ same type
TRPC5 p.Arg17Cys Uncertain significance ★ ⚠ same type
TRPC5 p.Arg17His Uncertain significance ★ ⚠ same type
TRPC5 p.Arg17Leu Uncertain significance ★ ⚠ same type
TRPC5 p.Arg222Cys Uncertain significance ★ ⚠ same type
TRPC5 p.Arg263Lys 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/trpc5-p-val233met (accessed [today's date]).

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