Is TRPC6 p.Ala404Val (c.1211C>T) pathogenic?

TRPC6 p.Ala404Val (c.1211C>T) is classified Benign in TRPC6 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1143); Common (popmax 12.2%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with focal segmental glomerulosclerosis.

What condition is associated with TRPC6 p.Ala404Val (c.1211C>T)?

TRPC6 p.Ala404Val (c.1211C>T) is associated with focal segmental glomerulosclerosis, focal segmental glomerulosclerosis 2 (ClinVar).

What do computational predictors say about TRPC6 p.Ala404Val (c.1211C>T)?

AlphaMissense predicts likely benign (score 0.1143) — an in-silico prediction, not a clinical call.

TRPC6 p.Ala404Val

Q: How common is TRPC6 p.Ala404Val (c.1211C>T) in the general population?

TRPC6 p.Ala404Val (c.1211C>T) is common (popmax 12.2%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1211C>T · rs36111323 · VCV259454

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1143 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 12.2%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

focal segmental glomerulosclerosis

Computational evidence

Protein change
AlphaMissense	0.1143	likely benign
REVEL	0.211	benign-leaning
SaProt	LLR -5.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -0.52, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 28 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	25.0	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 12.2% European (non-Finnish) · 144,070/1,179,950 alleles

Filtering AF 12.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.1%

Overall 11.1% 179,908/1,614,072 alleles · common exomes 167,280/1,461,790 · genomes 12,628/152,282 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	12.2%	8
South Asian	12.1%	8
Middle Eastern	11.2%	9
Remaining individualsnot grpmax-eligible	10.9%	9
Amishnot grpmax-eligible	10.9%	9
Ashkenazi Jewishnot grpmax-eligible	10.5%	9
Finnishnot grpmax-eligible	10%	10
Admixed American	6.32%	16
East Asian	5.23%	19
African / African-American	2.03%	49

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.Ala404Val
Coding: c.1211C>T
MANE Select: NM_004621
dbSNP: rs36111323
Type: single nucleotide variant
Location: chr11:101489019 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.98 · 6 PDB
Residue 404: a UniProt-annotated variant site (increases calcium ion transport)

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

Also linked: focal segmental glomerulosclerosis 2

Similar variants

TRPC6 p.Ala404= Likely benign ★★ same residue
TRPC6 p.Arg175Gln Likely pathogenic ★★ ⚠ same condition
TRPC6 p.Arg175Trp Pathogenic/Likely pathogenic ★★ same condition
TRPC6 p.Arg895Cys Pathogenic ★★ same condition
TRPC6 p.Arg895Leu Pathogenic ★★ same condition
TRPC6 p.Gln889Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
TRPC6 p.Glu897Lys Pathogenic/Likely pathogenic ★★ same condition
TRPC6 p.Pro112Gln Pathogenic ★★ ⚠ 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-ala404val (accessed [today's date]).

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