Is TRPC6 p.Ser355Arg (c.1065T>G) pathogenic?

TRPC6 p.Ser355Arg (c.1065T>G) is classified Conflicting classifications of pathogenicity in TRPC6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-12). AlphaMissense: likely benign (0.1517); Ultra-rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with TRPC6 p.Ser355Arg (c.1065T>G)?

TRPC6 p.Ser355Arg (c.1065T>G) is associated with Inborn genetic diseases, focal segmental glomerulosclerosis 2 (ClinVar).

How common is TRPC6 p.Ser355Arg (c.1065T>G) in the general population?

TRPC6 p.Ser355Arg (c.1065T>G) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about TRPC6 p.Ser355Arg (c.1065T>G)?

AlphaMissense predicts likely benign (score 0.1517) — an in-silico prediction, not a clinical call.

TRPC6 p.Ser355Arg

c.1065T>G · rs1036112313 · VCV1039436

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1517 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1517	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -6.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.67 · evaluated, not missing
Constraint at this position
Conservation	phyloP -5.1	GERP -4.1
Regional constraint	o/e 0.82	unconstrained · MANE · 28 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	0.09	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 0.01% Admixed American · 6/59,982 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000434% 7/1,613,880 alleles · ultra-rare exomes 7/1,461,848 · genomes 0/152,032 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,997
Remaining individualsnot grpmax-eligible	0.0016%	62,506

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.Ser355Arg
Coding: c.1065T>G
MANE Select: NM_004621
dbSNP: rs1036112313
Type: single nucleotide variant
Location: chr11:101491619 (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.Ser355Asn 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
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-ser355arg (accessed [today's date]).

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