Is TRPC5 p.Arg694His (c.2081G>A) pathogenic?

TRPC5 p.Arg694His (c.2081G>A) is classified Likely benign in TRPC5 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-05-26). AlphaMissense: likely benign (0.0789); Very rare (popmax 0.00186%, sas).

How common is TRPC5 p.Arg694His (c.2081G>A) in the general population?

TRPC5 p.Arg694His (c.2081G>A) is very rare (popmax 0.00186%, sas) (gnomAD).

What do computational predictors say about TRPC5 p.Arg694His (c.2081G>A)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

TRPC5 p.Arg694His

c.2081G>A · rs144130119 · VCV2291546

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	LLR -7.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 0.82, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 5,681 bp · p 0.061 · regional, not allelic
Overall
CADD	16.21	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 0.00186% South Asian · 1/53,649 alleles

Filtering AF 0.000722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00057%

Overall 0.00121% 13/1,076,315 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00186%	53,649
European (non-Finnish)	0.00135%	73,856

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.Arg694His
Coding: c.2081G>A
MANE Select: NM_012471
dbSNP: rs144130119
Type: single nucleotide variant
Location: chrX:111781954 (GRCh38)
Structure: AlphaFold pLDDT 73.82 · 30 PDB

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

Similar variants

TRPC5 p.Arg694Cys Uncertain significance ★ ⚠ same residue
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

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-arg694his (accessed [today's date]).

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