Is TRPC6 p.Cys43Phe (c.128G>T) pathogenic?

TRPC6 p.Cys43Phe (c.128G>T) is classified Uncertain significance in TRPC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-09). AlphaMissense: likely benign (0.0631); No allele count reported in gnomAD v4.1 (AN 1,593,766); Associated with focal segmental glomerulosclerosis 2.

What condition is associated with TRPC6 p.Cys43Phe (c.128G>T)?

TRPC6 p.Cys43Phe (c.128G>T) is associated with focal segmental glomerulosclerosis 2 (ClinVar).

How common is TRPC6 p.Cys43Phe (c.128G>T) in the general population?

TRPC6 p.Cys43Phe (c.128G>T) is no allele count reported in gnomAD v4.1 (AN 1,593,766) (gnomAD).

What do computational predictors say about TRPC6 p.Cys43Phe (c.128G>T)?

AlphaMissense predicts likely benign (score 0.0631) — an in-silico prediction, not a clinical call.

TRPC6 p.Cys43Phe

c.128G>T · rs2136909652 · VCV1691309

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0631 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,593,766)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

focal segmental glomerulosclerosis 2

Computational evidence

Protein change
AlphaMissense	0.0631	likely benign
REVEL	0.218	benign-leaning
SaProt	LLR -5.68	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 0.24	GERP 1.5
Regional constraint	o/e 1.42	unconstrained · MANE · 79 kb · p 8.7e-07 · regional, not allelic
Overall
CADD	19.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,593,766). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TRPC6
Protein: p.Cys43Phe
Coding: c.128G>T
MANE Select: NM_004621
dbSNP: rs2136909652
Type: single nucleotide variant
Location: chr11:101583376 (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 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRPC6 p.Cys43Ter Likely pathogenic ★ same residue
TRPC6 p.Cys43Trp 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-cys43phe (accessed [today's date]).

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