Is TRPC6 p.Pro15Ser (c.43C>T) pathogenic?

TRPC6 p.Pro15Ser (c.43C>T) is classified Benign in TRPC6 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0724); Common (popmax 12.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with focal segmental glomerulosclerosis 2.

What condition is associated with TRPC6 p.Pro15Ser (c.43C>T)?

TRPC6 p.Pro15Ser (c.43C>T) is associated with focal segmental glomerulosclerosis 2 (ClinVar).

What do computational predictors say about TRPC6 p.Pro15Ser (c.43C>T)?

AlphaMissense predicts likely benign (score 0.0724) — an in-silico prediction, not a clinical call.

TRPC6 p.Pro15Ser

Q: How common is TRPC6 p.Pro15Ser (c.43C>T) in the general population?

TRPC6 p.Pro15Ser (c.43C>T) is common (popmax 12.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.43C>T · rs3802829 · VCV259463

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0724 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 12.5%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

focal segmental glomerulosclerosis 2

Computational evidence

Protein change
AlphaMissense	0.0724	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -5.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -0.57, phastCons 1
Regional constraint	o/e 1.42	unconstrained · MANE · 79 kb · p 8.7e-07 · regional, not allelic
Overall
CADD	17.78	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 12.5% East Asian · 5,020/40,006 alleles

Filtering AF 12.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.1%

Overall 9.85% 150,811/1,531,530 alleles · common exomes 139,875/1,379,216 · genomes 10,936/152,314 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	12.5%	8
European (non-Finnish)	10.8%	9
Remaining individualsnot grpmax-eligible	10.2%	10
Middle Eastern	9.17%	11
Ashkenazi Jewishnot grpmax-eligible	8.93%	11
South Asian	7.23%	14
Admixed American	6.45%	15
Finnishnot grpmax-eligible	6.2%	16
Amishnot grpmax-eligible	4.06%	25
African / African-American	1.72%	58

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.Pro15Ser
Coding: c.43C>T
MANE Select: NM_004621
dbSNP: rs3802829
Type: single nucleotide variant
Location: chr11:101583461 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.98 · 6 PDB
Residue 15: the 'disordered' region; a UniProt-annotated variant site (in)

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

Disease context

focal segmental glomerulosclerosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRPC6 p.Pro15Ala Uncertain significance ★★ ⚠ same residue
TRPC6 p.Pro15Arg Uncertain significance ★ ⚠ 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

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-pro15ser (accessed [today's date]).

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