Is TRPC5 p.Leu738Ile (c.2212C>A) pathogenic?

TRPC5 p.Leu738Ile (c.2212C>A) is classified Conflicting classifications of pathogenicity in TRPC5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-13). AlphaMissense: ambiguous (0.4674); Ultra-rare (popmax 0.0618%, nfe).

How common is TRPC5 p.Leu738Ile (c.2212C>A) in the general population?

TRPC5 p.Leu738Ile (c.2212C>A) is ultra-rare (popmax 0.0618%, nfe) (gnomAD).

What do computational predictors say about TRPC5 p.Leu738Ile (c.2212C>A)?

AlphaMissense predicts ambiguous (score 0.4674) — an in-silico prediction, not a clinical call.

TRPC5 p.Leu738Ile

c.2212C>A · rs145407228 · VCV2661215

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4674 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0618%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4674	ambiguous
REVEL	0.348	indeterminate
SaProt	LLR -4.97	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -0.67, phastCons 0.99
Regional constraint	o/e 0.87	unconstrained · MANE · 5,681 bp · p 0.061 · regional, not allelic
Overall
CADD	20.6	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 0.0618% European (non-Finnish) · 549/888,232 alleles

Filtering AF 0.0575% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0557%

Overall 0.0476% 570/1,197,706 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0618%	1,618
Remaining individualsnot grpmax-eligible	0.0339%	2,949
Middle Eastern	0.0231%	4,325
Admixed American	0.00674%	14,845
African / African-American	0.00176%	56,859

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.Leu738Ile
Coding: c.2212C>A
MANE Select: NM_012471
dbSNP: rs145407228
Type: single nucleotide variant
Location: chrX:111779005 (GRCh38)
Structure: AlphaFold pLDDT 73.82 · 30 PDB
Residue 738: a UniProt-annotated variant site (found in a patient with mental disorder and obesity; uncertain significance; no effect on protein levels; does not affect cell membrane localization; strongly reduces channel activity)

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-leu738ile (accessed [today's date]).

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