Is TRPC3 p.Ile259= (c.777C>T) pathogenic?

TRPC3 p.Ile259= (c.777C>T) is classified Likely benign in TRPC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-27). Very rare (popmax 0.0022%, sas).

How common is TRPC3 p.Ile259= (c.777C>T) in the general population?

TRPC3 p.Ile259= (c.777C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

TRPC3 p.Ile259=

c.777C>T · VCV4968409

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -0.55, phastCons 1
Overall
CADD	12.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,086 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000186% 3/1,614,198 alleles · very rare exomes 3/1,461,894 · genomes 0/152,304 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,543
Finnishnot grpmax-eligible	0.00156%	64,042

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: TRPC3
Protein: p.Ile259=
Coding: c.777C>T
MANE Select: NM_001130698
Type: single nucleotide variant
Location: chr4:121932481 (GRCh38)
Gene constraint: LOEUF 0.751 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.42 · 19 PDB

Full TRPC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPC3 p.Arg381Cys Uncertain significance ★★ same type
TRPC3 p.Arg795Gln Uncertain significance ★★ same type
TRPC3 p.Asn728Ser Uncertain significance ★★ same type
TRPC3 p.Glu901Lys Uncertain significance ★★ same type
TRPC3 p.Ile629Val Uncertain significance ★★ same type
TRPC3 p.Leu905Val Uncertain significance ★★ same type
TRPC3 p.Lys710Arg Uncertain significance ★★ same type
TRPC3 p.Pro444Ser 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/trpc3-p-ile259 (accessed [today's date]).

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