Is TRPC1 p.Pro681Ser (c.2041C>T) pathogenic?

TRPC1 p.Pro681Ser (c.2041C>T) is classified Uncertain significance in TRPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-07). AlphaMissense: likely pathogenic (0.9979); Very rare (popmax 0.00167%, amr).

How common is TRPC1 p.Pro681Ser (c.2041C>T) in the general population?

TRPC1 p.Pro681Ser (c.2041C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TRPC1 p.Pro681Ser (c.2041C>T)?

AlphaMissense predicts likely pathogenic (score 0.9979) — an in-silico prediction, not a clinical call.

TRPC1 p.Pro681Ser

c.2041C>T · VCV3810939

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9979	likely pathogenic · top 4% in TRPC1
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -9.81	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 1,726 bp · p 0.002 · regional, not allelic
Overall
CADD	27.1	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 0.00167% Admixed American · 1/59,946 alleles

Overall 0.000124% 2/1,613,696 alleles · very rare exomes 1/1,461,538 · genomes 1/152,158 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,946
Remaining individualsnot grpmax-eligible	0.0016%	62,470

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.Pro681Ser
Coding: c.2041C>T
MANE Select: NM_001251845
Type: single nucleotide variant
Location: chr3:142804517 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.87 · 4 PDB
Residue 681: a turn

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-pro681ser (accessed [today's date]).

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