Is TRPC6 p.Arg91Cys (c.271C>T) pathogenic?

TRPC6 p.Arg91Cys (c.271C>T) is classified Conflicting classifications of pathogenicity in TRPC6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-01). AlphaMissense: likely benign (0.1276); Ultra-rare (popmax 0.0336%, mid); Associated with Inborn genetic diseases.

What condition is associated with TRPC6 p.Arg91Cys (c.271C>T)?

TRPC6 p.Arg91Cys (c.271C>T) is associated with Inborn genetic diseases, focal segmental glomerulosclerosis 2 (ClinVar).

How common is TRPC6 p.Arg91Cys (c.271C>T) in the general population?

TRPC6 p.Arg91Cys (c.271C>T) is ultra-rare (popmax 0.0336%, mid) (gnomAD).

What do computational predictors say about TRPC6 p.Arg91Cys (c.271C>T)?

AlphaMissense predicts likely benign (score 0.1276) — an in-silico prediction, not a clinical call.

TRPC6 p.Arg91Cys

c.271C>T · rs200186406 · VCV1047192

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1276 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0336%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1276	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -8.66	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 9.9	GERP 2, phastCons 1
Regional constraint	o/e 1.42	unconstrained · MANE · 79 kb · p 8.7e-07 · regional, not allelic
Overall
CADD	24.9	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 0.0336% Middle Eastern · 2/5,950 alleles

Filtering AF 0.00592% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.00508% 81/1,594,254 alleles · ultra-rare exomes 77/1,442,150 · genomes 4/152,104 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0336%	2,975
Admixed American	0.00682%	14,655
European (non-Finnish)	0.00625%	16,010
Ashkenazi Jewishnot grpmax-eligible	0.00356%	28,116
African / African-American	0.00134%	74,384

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.Arg91Cys
Coding: c.271C>T
MANE Select: NM_004621
dbSNP: rs200186406
Type: single nucleotide variant
Location: chr11:101504698 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: focal segmental glomerulosclerosis 2

Similar variants

TRPC6 p.Arg91= Likely benign ★★ same residue
TRPC6 p.Arg91Leu Uncertain significance ★ ⚠ same residue
TRPC6 p.Arg91His 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

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-arg91cys (accessed [today's date]).

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