Is TRPC4 p.Arg313His (c.938G>A) pathogenic?

TRPC4 p.Arg313His (c.938G>A) is classified Uncertain significance in TRPC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-03). AlphaMissense: ambiguous (0.3677); Very rare (popmax 0.00267%, afr).

How common is TRPC4 p.Arg313His (c.938G>A) in the general population?

TRPC4 p.Arg313His (c.938G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TRPC4 p.Arg313His (c.938G>A)?

AlphaMissense predicts ambiguous (score 0.3677) — an in-silico prediction, not a clinical call.

TRPC4 p.Arg313His

c.938G>A · rs147415849 · VCV2322196

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3677 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
AlphaMissense	0.3677	ambiguous
REVEL	0.337	indeterminate
SaProt	LLR -5.59	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP 0.24, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 95 kb · p 2.2e-17 · regional, not allelic
Overall
CADD	29.7	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 0.00267% African / African-American · 2/74,872 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000558% 9/1,613,820 alleles · very rare exomes 7/1,461,766 · genomes 2/152,054 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,436
European (non-Finnish)	0.000593%	168,565

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.Arg313His
Coding: c.938G>A
MANE Select: NM_016179
dbSNP: rs147415849
Type: single nucleotide variant
Location: chr13:37692295 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.71 · 3 PDB
Residue 313: an α-helix

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

Similar variants

TRPC4 p.Arg976= Benign ★★ same type
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

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-arg313his (accessed [today's date]).

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