Is ARHGEF1 p.Pro773Ser (c.2317C>T) pathogenic?

ARHGEF1 p.Pro773Ser (c.2317C>T) is classified Uncertain significance in ARHGEF1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.0692); Ultra-rare (popmax 0.0263%, nfe).

How common is ARHGEF1 p.Pro773Ser (c.2317C>T) in the general population?

ARHGEF1 p.Pro773Ser (c.2317C>T) is ultra-rare (popmax 0.0263%, nfe) (gnomAD).

What do computational predictors say about ARHGEF1 p.Pro773Ser (c.2317C>T)?

AlphaMissense predicts likely benign (score 0.0692) — an in-silico prediction, not a clinical call.

ARHGEF1 p.Pro773Ser

c.2317C>T · rs375701795 · VCV1448900

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0692 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0263%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0692	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -6.60	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 0.26	GERP -1.2, phastCons 0.74
Regional constraint	o/e 0.56	unconstrained · MANE · 6,691 bp · p 1e-22 · regional, not allelic
Overall
CADD	13.59	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0263% European (non-Finnish) · 310/1,179,864 alleles

Filtering AF 0.0238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0229%

Overall 0.0203% 327/1,613,598 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0263%	3,806
Remaining individualsnot grpmax-eligible	0.0192%	5,206
African / African-American	0.00667%	14,982

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: ARHGEF1
Protein: p.Pro773Ser
Coding: c.2317C>T
MANE Select: NM_004706
dbSNP: rs375701795
Type: single nucleotide variant
Location: chr19:41905242 (GRCh38)
Gene constraint: LOEUF 0.459 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.49 · 7 PDB
Residue 773: a UniProt-annotated variant site (in imd62; impairs rhoa gtpase activation and gna12- and gna13-mediated signaling; reduces actin polymerization); the 'disordered' region

Full ARHGEF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGEF1 c.1738+5C>T Uncertain significance ★★ same type
ARHGEF1 c.644+6G>T Uncertain significance ★★ same type
ARHGEF1 c.-20+1180T>A Uncertain significance ★★ same type
ARHGEF1 c.-20+1201G>C Uncertain significance ★★ same type
ARHGEF1 p.Ala119Thr Uncertain significance ★★ ⚠ same type
ARHGEF1 p.Ala272Thr Uncertain significance ★★ ⚠ same type
ARHGEF1 p.Ala361Val Uncertain significance ★★ ⚠ same type
ARHGEF1 p.Ala528Val 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/arhgef1-p-pro773ser (accessed [today's date]).

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