Is ARFGAP2 p.Ala227Thr (c.679G>A) pathogenic?

ARFGAP2 p.Ala227Thr (c.679G>A) is classified Uncertain significance in ARFGAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: likely benign (0.0852); Very rare (popmax 0.00223%, eas).

How common is ARFGAP2 p.Ala227Thr (c.679G>A) in the general population?

ARFGAP2 p.Ala227Thr (c.679G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ARFGAP2 p.Ala227Thr (c.679G>A)?

AlphaMissense predicts likely benign (score 0.0852) — an in-silico prediction, not a clinical call.

ARFGAP2 p.Ala227Thr

c.679G>A · VCV3420350

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0852 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0852	likely benign
REVEL	0.22	benign-leaning
SaProt	LLR -10.04	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 11 kb · p 0.12 · regional, not allelic
Overall
CADD	24.4	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 0.00223% East Asian · 1/44,886 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000479% 7/1,461,298 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
Remaining individualsnot grpmax-eligible	0.0016%	62,496
European (non-Finnish)	0.000424%	236,009

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: ARFGAP2
Protein: p.Ala227Thr
Coding: c.679G>A
MANE Select: NM_032389
Type: single nucleotide variant
Location: chr11:47171794 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.19 · 1 PDB
Residue 227: the 'required for interaction with coatomer' region; the 'disordered' region

Full ARFGAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARFGAP2 p.Ala259Thr Uncertain significance ★ ⚠ same type
ARFGAP2 p.Ala266Val Uncertain significance ★ ⚠ same type
ARFGAP2 p.Ala272Thr Uncertain significance ★ ⚠ same type
ARFGAP2 p.Ala421Val Uncertain significance ★ ⚠ same type
ARFGAP2 p.Ala443Val Uncertain significance ★ ⚠ same type
ARFGAP2 p.Ala500Pro Uncertain significance ★ ⚠ same type
ARFGAP2 p.Arg119Trp Uncertain significance ★ ⚠ same type
ARFGAP2 p.Arg255Gly 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/arfgap2-p-ala227thr (accessed [today's date]).

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