Is TRPC7 p.Arg409Gln (c.1226G>A) pathogenic?

TRPC7 p.Arg409Gln (c.1226G>A) is classified Uncertain significance in TRPC7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-02). AlphaMissense: likely pathogenic (0.798); Very rare (popmax 0.00446%, eas).

How common is TRPC7 p.Arg409Gln (c.1226G>A) in the general population?

TRPC7 p.Arg409Gln (c.1226G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about TRPC7 p.Arg409Gln (c.1226G>A)?

AlphaMissense predicts likely pathogenic (score 0.798) — an in-silico prediction, not a clinical call.

TRPC7 p.Arg409Gln

c.1226G>A · rs1196926705 · VCV2615341

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.798 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.798	likely pathogenic
REVEL	0.582	indeterminate
SaProt	LLR -11.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 7.1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 105 kb · p 0.26 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00112% 18/1,613,700 alleles · very rare exomes 15/1,461,592 · genomes 3/152,108 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,440
Remaining individualsnot grpmax-eligible	0.0016%	62,454
African / African-American	0.00134%	74,872
European (non-Finnish)	0.0011%	90,756
South Asian	0.0011%	91,070

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: TRPC7
Protein: p.Arg409Gln
Coding: c.1226G>A
MANE Select: NM_020389
dbSNP: rs1196926705
Type: single nucleotide variant
Location: chr5:136266339 (GRCh38)
Gene constraint: LOEUF 0.596 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.97

Full TRPC7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPC7 p.Ala109Val Uncertain significance ★ ⚠ same type
TRPC7 p.Ala228Thr Uncertain significance ★ same type
TRPC7 p.Ala30Ser Uncertain significance ★ ⚠ same type
TRPC7 p.Ala484Val Uncertain significance ★ ⚠ same type
TRPC7 p.Ala545Thr Uncertain significance ★ ⚠ same type
TRPC7 p.Ala607Thr Uncertain significance ★ ⚠ same type
TRPC7 p.Ala737Thr Uncertain significance ★ ⚠ same type
TRPC7 p.Ala737Val 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/trpc7-p-arg409gln (accessed [today's date]).

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