Is TRPC5 p.Ile337Thr (c.1010T>C) pathogenic?

TRPC5 p.Ile337Thr (c.1010T>C) is classified Uncertain significance in TRPC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: ambiguous (0.3495); Ultra-rare (popmax 0.0229%, mid).

How common is TRPC5 p.Ile337Thr (c.1010T>C) in the general population?

TRPC5 p.Ile337Thr (c.1010T>C) is ultra-rare (popmax 0.0229%, mid) (gnomAD).

What do computational predictors say about TRPC5 p.Ile337Thr (c.1010T>C)?

AlphaMissense predicts ambiguous (score 0.3495) — an in-silico prediction, not a clinical call.

TRPC5 p.Ile337Thr

c.1010T>C · VCV3974146

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3495 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3495	ambiguous
REVEL	0.649	pathogenic-leaning
SaProt	LLR -12.12	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 131 kb · p 1e-26 · regional, not allelic
Overall
CADD	25.5	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 0.0229% Middle Eastern · 1/4,374 alleles

Filtering AF 0.000325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000209%

Overall 0.000909% 11/1,210,028 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0229%	4,374
Remaining individualsnot grpmax-eligible	0.0021%	47,603
South Asian	0.00176%	56,770
African / African-American	0.00175%	57,137
European (non-Finnish)	0.000782%	127,891

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.Ile337Thr
Coding: c.1010T>C
MANE Select: NM_012471
Type: single nucleotide variant
Location: chrX:111853997 (GRCh38)
Structure: AlphaFold pLDDT 73.82 · 30 PDB
Residue 337: 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-ile337thr (accessed [today's date]).

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