Is TRPC4 p.Arg976= (c.2928A>G) pathogenic?

TRPC4 p.Arg976= (c.2928A>G) is classified Benign in TRPC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). Common (popmax 9.72%, afr) — too common for a highly-penetrant pathogenic allele.

TRPC4 p.Arg976=

Q: How common is TRPC4 p.Arg976= (c.2928A>G) in the general population?

TRPC4 p.Arg976= (c.2928A>G) is common (popmax 9.72%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2928A>G · rs731860 · VCV778695

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 9.72%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.094	GERP -3.2, phastCons 0.12
Overall
CADD	0.692	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.72% African / African-American · 7,267/74,794 alleles

Filtering AF 9.53% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.45%

Overall 0.528% 8,503/1,609,486 alleles · common exomes 4,232/1,457,282 · genomes 4,271/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.72%	10
Middle Eastern	0.98%	102
Admixed American	0.816%	123
Remaining individualsnot grpmax-eligible	0.796%	126
South Asian	0.0243%	4,118
European (non-Finnish)	0.0144%	6,967
Finnishnot grpmax-eligible	0.00313%	31,902
East Asian	0.00223%	44,832

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: TRPC4
Protein: p.Arg976=
Coding: c.2928A>G
MANE Select: NM_016179
dbSNP: rs731860
Type: single nucleotide variant
Location: chr13:37636909 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.71 · 3 PDB
Residue 976: the 'interaction with itpr1, itpr2 and itpr3' region; the 'pdz-binding domain' region

Full TRPC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPC4 p.Cys333= Benign ★★ same type
TRPC4 c.379-2A>T Pathogenic ★ same type
TRPC4 p.Ala327Val Uncertain significance ★ ⚠ same type
TRPC4 p.Ala484Thr Uncertain significance ★ ⚠ same type
TRPC4 p.Ala697Thr Uncertain significance ★ same type
TRPC4 p.Ala720Glu Uncertain significance ★ ⚠ same type
TRPC4 p.Ala808Thr Uncertain significance ★ ⚠ same type
TRPC4 p.Ala856Ser Uncertain significance ★ ⚠ 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/trpc4-p-arg976 (accessed [today's date]).

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