Is TRPC1 p.Ser22Pro (c.64T>C) pathogenic?

TRPC1 p.Ser22Pro (c.64T>C) is classified Uncertain significance in TRPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: likely benign (0.0778); Ultra-rare (popmax 0.0671%, sas).

How common is TRPC1 p.Ser22Pro (c.64T>C) in the general population?

TRPC1 p.Ser22Pro (c.64T>C) is ultra-rare (popmax 0.0671%, sas) (gnomAD).

What do computational predictors say about TRPC1 p.Ser22Pro (c.64T>C)?

AlphaMissense predicts likely benign (score 0.0778) — an in-silico prediction, not a clinical call.

TRPC1 p.Ser22Pro

c.64T>C · rs760081567 · VCV2254223

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0778 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0671%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0778	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.1	GERP 0.45, phastCons 1
Regional constraint	o/e 1.24	unconstrained · MANE · 12 kb · p 0.0078 · regional, not allelic
Overall
CADD	22.9	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 0.0671% South Asian · 61/90,862 alleles

Filtering AF 0.0536% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0487%

Overall 0.00409% 66/1,611,784 alleles · ultra-rare exomes 66/1,459,764 · genomes 0/152,020 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0671%	1,490
Remaining individualsnot grpmax-eligible	0.00802%	12,471

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: TRPC1
Protein: p.Ser22Pro
Coding: c.64T>C
MANE Select: NM_001251845
dbSNP: rs760081567
Type: single nucleotide variant
Location: chr3:142724623 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.87 · 4 PDB
Residue 22: the 'disordered' region

Full TRPC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPC1 p.Ala224Val Uncertain significance ★ ⚠ same type
TRPC1 p.Ala623Thr Uncertain significance ★ ⚠ same type
TRPC1 p.Ala623Val Uncertain significance ★ ⚠ same type
TRPC1 p.Ala653Val Uncertain significance ★ ⚠ same type
TRPC1 p.Ala787Asp Uncertain significance ★ ⚠ same type
TRPC1 p.Arg169Cys Uncertain significance ★ ⚠ same type
TRPC1 p.Arg277Gln Uncertain significance ★ ⚠ same type
TRPC1 p.Arg455Cys 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/trpc1-p-ser22pro (accessed [today's date]).

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