Is TRPC6 p.Val126Phe (c.376G>T) pathogenic?

TRPC6 p.Val126Phe (c.376G>T) is classified Uncertain significance in TRPC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-23). AlphaMissense: likely benign (0.2114); Very rare (popmax 0.00878%, sas); Associated with focal segmental glomerulosclerosis.

What condition is associated with TRPC6 p.Val126Phe (c.376G>T)?

TRPC6 p.Val126Phe (c.376G>T) is associated with focal segmental glomerulosclerosis (ClinVar).

How common is TRPC6 p.Val126Phe (c.376G>T) in the general population?

TRPC6 p.Val126Phe (c.376G>T) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about TRPC6 p.Val126Phe (c.376G>T)?

AlphaMissense predicts likely benign (score 0.2114) — an in-silico prediction, not a clinical call.

TRPC6 p.Val126Phe

c.376G>T · rs370656422 · VCV1712382

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2114 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

focal segmental glomerulosclerosis

Computational evidence

Protein change
AlphaMissense	0.2114	likely benign
REVEL	0.501	indeterminate
SaProt	LLR -11.34	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 28 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	23.3	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 0.00878% South Asian · 8/91,086 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00062% 10/1,613,992 alleles · very rare exomes 10/1,461,686 · genomes 0/152,306 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,386
Remaining individualsnot grpmax-eligible	0.0016%	62,510
African / African-American	0.00133%	75,018

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: TRPC6
Protein: p.Val126Phe
Coding: c.376G>T
MANE Select: NM_004621
dbSNP: rs370656422
Type: single nucleotide variant
Location: chr11:101504593 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.98 · 6 PDB

Full TRPC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

focal segmental glomerulosclerosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRPC6 p.Val126Ile Uncertain significance ★ ⚠ same residue
TRPC6 p.Ala404Val Benign ★★ same condition
TRPC6 p.Asn696= Benign/Likely benign ★★ same condition
TRPC6 p.Gly279= Benign/Likely benign ★★ same condition
TRPC6 p.Leu332= Benign/Likely benign ★★ same condition
TRPC6 p.Thr714= Benign/Likely benign ★★ same condition
TRPC6 p.Tyr705= Benign/Likely benign ★★ same condition
TRPC6 p.Arg399Gln Conflicting classifications of pathogenicity ★ ⚠ same condition

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/trpc6-p-val126phe (accessed [today's date]).

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