Is ARHGEF4 p.Ala1237Ser (c.3709G>T) pathogenic?

ARHGEF4 p.Ala1237Ser (c.3709G>T) is classified Uncertain significance in ARHGEF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-04). AlphaMissense: likely benign (0.0747); Very rare (popmax 0.00398%, nfe).

How common is ARHGEF4 p.Ala1237Ser (c.3709G>T) in the general population?

ARHGEF4 p.Ala1237Ser (c.3709G>T) is very rare (popmax 0.00398%, nfe) (gnomAD).

What do computational predictors say about ARHGEF4 p.Ala1237Ser (c.3709G>T)?

AlphaMissense predicts likely benign (score 0.0747) — an in-silico prediction, not a clinical call.

ARHGEF4 p.Ala1237Ser

c.3709G>T · rs776243134 · VCV2551498

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0747 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00398%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0747	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.38	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 1.1	GERP -2.3, phastCons 0.003
Regional constraint	o/e 1.11	unconstrained · MANE · 124 kb · p 3e-05 · regional, not allelic
Overall
CADD	3.318	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 A51S vs ClinVar A1237S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00398% European (non-Finnish) · 47/1,180,038 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00297% 48/1,614,046 alleles · very rare exomes 40/1,461,828 · genomes 8/152,218 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00398%	25,107
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: ARHGEF4
Protein: p.Ala1237Ser
Coding: c.3709G>T
MANE Select: NM_001367493
dbSNP: rs776243134
Type: single nucleotide variant
Location: chr2:130931108 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 70.45 · 4 PDB

Full ARHGEF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGEF4 p.Glu1416= Benign ★★ same type
ARHGEF4 p.Trp1321Cys Benign ★★ same type
ARHGEF4 p.Ala1211Ser Uncertain significance ★ ⚠ same type
ARHGEF4 p.Ala1224Ser Uncertain significance ★ ⚠ same type
ARHGEF4 p.Ala1423Thr Uncertain significance ★ ⚠ same type
ARHGEF4 p.Ala1431Ser Uncertain significance ★ ⚠ same type
ARHGEF4 p.Ala1431Thr Uncertain significance ★ ⚠ same type
ARHGEF4 p.Ala1448Val 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/arhgef4-p-ala1237ser (accessed [today's date]).

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