Is TRPC6 p.Ser28Ile (c.83G>T) pathogenic?

TRPC6 p.Ser28Ile (c.83G>T) is classified Uncertain significance in TRPC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-18). AlphaMissense: likely benign (0.2661); Very rare (popmax 0.0018%, amr); Associated with Inborn genetic diseases.

What condition is associated with TRPC6 p.Ser28Ile (c.83G>T)?

TRPC6 p.Ser28Ile (c.83G>T) is associated with Inborn genetic diseases (ClinVar).

How common is TRPC6 p.Ser28Ile (c.83G>T) in the general population?

TRPC6 p.Ser28Ile (c.83G>T) is very rare (popmax 0.0018%, amr) (gnomAD).

What do computational predictors say about TRPC6 p.Ser28Ile (c.83G>T)?

AlphaMissense predicts likely benign (score 0.2661) — an in-silico prediction, not a clinical call.

TRPC6 p.Ser28Ile

c.83G>T · VCV3390546

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2661 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0018%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2661	likely benign
REVEL	0.427	indeterminate
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.1	GERP 1.3, phastCons 1
Regional constraint	o/e 1.42	unconstrained · MANE · 79 kb · p 8.7e-07 · regional, not allelic
Overall
CADD	27.3	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 0.0018% Admixed American · 1/55,468 alleles

Overall 0.000128% 2/1,567,978 alleles · very rare exomes 1/1,415,720 · genomes 1/152,258 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0018%	55,468
Finnishnot grpmax-eligible	0.0017%	58,972

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.Ser28Ile
Coding: c.83G>T
MANE Select: NM_004621
Type: single nucleotide variant
Location: chr11:101583421 (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

Similar variants

TRPC6 p.Ser28Arg Uncertain significance ★ same residue
TRPC6 p.Glu897Lys Pathogenic/Likely pathogenic ★★ same condition
TRPC6 p.Ala369Asp Uncertain significance ★★ ⚠ same condition
TRPC6 p.Ala538Thr Uncertain significance ★★ ⚠ same condition
TRPC6 p.Arg73Leu Uncertain significance ★★ ⚠ same condition
TRPC6 p.Asp317Glu Uncertain significance ★★ ⚠ same condition
TRPC6 p.Gln3Arg Uncertain significance ★★ ⚠ same condition
TRPC6 p.Glu200Asp Uncertain significance ★★ ⚠ 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-ser28ile (accessed [today's date]).

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