Is ARFGAP2 p.Arg339His (c.1016G>A) pathogenic?

ARFGAP2 p.Arg339His (c.1016G>A) is classified Benign in ARFGAP2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-12). AlphaMissense: likely benign (0.1284); Low-frequency (popmax 2.33%, afr); Associated with ARFGAP2-related disorder.

What condition is associated with ARFGAP2 p.Arg339His (c.1016G>A)?

ARFGAP2 p.Arg339His (c.1016G>A) is associated with ARFGAP2-related disorder (ClinVar).

How common is ARFGAP2 p.Arg339His (c.1016G>A) in the general population?

ARFGAP2 p.Arg339His (c.1016G>A) is low-frequency (popmax 2.33%, afr) (gnomAD).

What do computational predictors say about ARFGAP2 p.Arg339His (c.1016G>A)?

AlphaMissense predicts likely benign (score 0.1284) — an in-silico prediction, not a clinical call.

ARFGAP2 p.Arg339His

c.1016G>A · rs34662994 · VCV3055789

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1284 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.33%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ARFGAP2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1284	likely benign
REVEL	0.265	benign-leaning
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 11 kb · p 0.12 · regional, not allelic
Overall
CADD	24.8	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 2.33% African / African-American · 1,750/75,060 alleles

Filtering AF 2.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.2%

Overall 0.126% 2,039/1,614,238 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.33%	43
Middle Eastern	0.247%	404
Remaining individualsnot grpmax-eligible	0.189%	530
Admixed American	0.133%	750
Ashkenazi Jewishnot grpmax-eligible	0.0811%	1,234
East Asian	0.0223%	4,489
South Asian	0.00549%	18,217
European (non-Finnish)	0.00314%	31,893

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.Arg339His
Coding: c.1016G>A
MANE Select: NM_032389
dbSNP: rs34662994
Type: single nucleotide variant
Location: chr11:47168177 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.19 · 1 PDB
Residue 339: a UniProt-annotated variant site (in); the 'required for interaction with coatomer' region

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

Disease context

ARFGAP2-related disorder

Similar variants

ARFGAP2 p.Arg339Leu Likely benign same residue
ARFGAP2 c.191+6C>T Likely benign same condition
ARFGAP2 c.265-10T>C Likely benign same condition
ARFGAP2 c.396+7G>A Likely benign same condition
ARFGAP2 c.809+6T>C Benign same condition
ARFGAP2 c.-9G>A Likely benign same condition
ARFGAP2 c.*4G>A Benign same condition
ARFGAP2 p.Ala266= Benign same condition

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-arg339his (accessed [today's date]).

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