Is TRPC6 p.Phe537= (c.1611C>T) pathogenic?

TRPC6 p.Phe537= (c.1611C>T) is classified Likely benign in TRPC6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-08-28). Ultra-rare (popmax 0.0186%, nfe); Associated with nephrotic syndrome.

What condition is associated with TRPC6 p.Phe537= (c.1611C>T)?

TRPC6 p.Phe537= (c.1611C>T) is associated with nephrotic syndrome (ClinVar).

How common is TRPC6 p.Phe537= (c.1611C>T) in the general population?

TRPC6 p.Phe537= (c.1611C>T) is ultra-rare (popmax 0.0186%, nfe) (gnomAD).

TRPC6 p.Phe537=

c.1611C>T · rs150183033 · VCV988134

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0186%, nfe)

Conditions

nephrotic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.12	GERP -4.1, phastCons 0.14
Overall
CADD	4.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0186% European (non-Finnish) · 220/1,179,990 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0158%

Overall 0.0161% 260/1,614,020 alleles · ultra-rare exomes 241/1,461,846 · genomes 19/152,174 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0368%	2,717
European (non-Finnish)grpmax	0.0186%	5,364
African / African-American	0.008%	12,499
East Asian	0.00669%	14,959
South Asian	0.00549%	18,215
Admixed American	0.005%	19,999

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe537=
Coding: c.1611C>T
MANE Select: NM_004621
dbSNP: rs150183033
Type: single nucleotide variant
Location: chr11:101476434 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.98 · 6 PDB
Residue 537: an α-helix

Full TRPC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephrotic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRPC6 p.Arg175Trp Pathogenic/Likely pathogenic ★★ same condition
TRPC6 p.Arg895Cys Pathogenic ★★ same condition
TRPC6 p.Arg895Leu Pathogenic ★★ same condition
TRPC6 p.Arg215Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
TRPC6 c.2645-1G>A Uncertain significance same condition
TRPC6 p.Arg175Gln Likely pathogenic ★★ ⚠ same type
TRPC6 p.Gln869Ter Pathogenic/Likely pathogenic ★★ same type
TRPC6 p.Gln889Lys Pathogenic/Likely pathogenic ★★ ⚠ same type

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-phe537 (accessed [today's date]).

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