Is TRPC6 p.Val706Ile (c.2116G>A) pathogenic?

TRPC6 p.Val706Ile (c.2116G>A) is classified Uncertain significance in TRPC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-29). AlphaMissense: likely benign (0.0935); Very rare (popmax 0.00334%, amr); Associated with focal segmental glomerulosclerosis 2.

What condition is associated with TRPC6 p.Val706Ile (c.2116G>A)?

TRPC6 p.Val706Ile (c.2116G>A) is associated with focal segmental glomerulosclerosis 2 (ClinVar).

How common is TRPC6 p.Val706Ile (c.2116G>A) in the general population?

TRPC6 p.Val706Ile (c.2116G>A) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about TRPC6 p.Val706Ile (c.2116G>A)?

AlphaMissense predicts likely benign (score 0.0935) — an in-silico prediction, not a clinical call.

TRPC6 p.Val706Ile

c.2116G>A · VCV3598790

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

focal segmental glomerulosclerosis 2

Computational evidence

Protein change
AlphaMissense	0.0935	likely benign
REVEL	0.516	indeterminate
SaProt	LLR -5.90	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 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 4,942 bp · p 1.5e-08 · regional, not allelic
Overall
CADD	22.5	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

Grpmax group 0.00334% Admixed American · 2/59,956 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000372% 6/1,613,008 alleles · very rare exomes 5/1,460,916 · genomes 1/152,092 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,978
South Asian	0.0022%	45,501
African / African-American	0.00134%	74,870
European (non-Finnish)	8.48e-05%	1,179,528

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.Val706Ile
Coding: c.2116G>A
MANE Select: NM_004621
Type: single nucleotide variant
Location: chr11:101472226 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.98 · 6 PDB
Residue 706: an α-helix

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.Val706Phe 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-val706ile (accessed [today's date]).

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