Is ARHGEF7 p.Pro583Ala (c.1747C>G) pathogenic?

ARHGEF7 p.Pro583Ala (c.1747C>G) is classified Uncertain significance in ARHGEF7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-19). AlphaMissense: likely benign (0.0793); Very rare (popmax 0.00227%, eas).

How common is ARHGEF7 p.Pro583Ala (c.1747C>G) in the general population?

ARHGEF7 p.Pro583Ala (c.1747C>G) is very rare (popmax 0.00227%, eas) (gnomAD).

What do computational predictors say about ARHGEF7 p.Pro583Ala (c.1747C>G)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

ARHGEF7 p.Pro583Ala

c.1747C>G · VCV4143064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00227%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -7.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 81 kb · p 2.6e-07 · regional, not allelic
Overall
CADD	23.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P604A vs ClinVar P583A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00227% East Asian · 1/44,068 alleles

Filtering AF 0.000294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000213%

Overall 0.000625% 9/1,440,204 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00227%	44,068
European (non-Finnish)	0.000684%	146,260

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: ARHGEF7
Protein: p.Pro583Ala
Coding: c.1747C>G
MANE Select: NM_001354046
Type: single nucleotide variant
Location: chr13:111283160 (GRCh38)
Gene constraint: LOEUF 0.53 · pLI 0.78 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.31 · 4 PDB
Residue 583: the 'disordered' region

Full ARHGEF7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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PAK3 c.830+6T>A Uncertain significance ★★ same type
PAK3 p.Ala490Thr Uncertain significance ★★ ⚠ same type
PAK3 p.Arg493Cys Uncertain significance ★★ ⚠ same type
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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/arhgef7-p-pro583ala (accessed [today's date]).

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