Is ARFGAP2 p.Arg339Leu (c.1016G>T) pathogenic?

ARFGAP2 p.Arg339Leu (c.1016G>T) is classified Likely benign in ARFGAP2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-12-18). AlphaMissense: ambiguous (0.3559); Rare (popmax 0.515%, eas); Associated with ARFGAP2-related disorder.

What condition is associated with ARFGAP2 p.Arg339Leu (c.1016G>T)?

ARFGAP2 p.Arg339Leu (c.1016G>T) is associated with ARFGAP2-related disorder (ClinVar).

How common is ARFGAP2 p.Arg339Leu (c.1016G>T) in the general population?

ARFGAP2 p.Arg339Leu (c.1016G>T) is rare (popmax 0.515%, eas) (gnomAD).

What do computational predictors say about ARFGAP2 p.Arg339Leu (c.1016G>T)?

AlphaMissense predicts ambiguous (score 0.3559) — an in-silico prediction, not a clinical call.

ARFGAP2 p.Arg339Leu

c.1016G>T · rs34662994 · VCV3048473

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3559 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.515%, eas)

Conditions

ARFGAP2-related disorder

Computational evidence

Protein change
AlphaMissense	0.3559	ambiguous
REVEL	0.374	indeterminate
SaProt	LLR -6.86	tolerated
Splicing
SpliceAI	Δ0.35	acceptor gain · deltas
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	26.9	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 0.515% East Asian · 231/44,890 alleles

Filtering AF 0.46% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.439%

Overall 0.0183% 295/1,614,236 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.515%	194
Remaining individualsnot grpmax-eligible	0.0352%	2,841
South Asian	0.0187%	5,358
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00195%	51,307
Admixed American	0.00167%	60,022

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.Arg339Leu
Coding: c.1016G>T
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.Arg339His 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-arg339leu (accessed [today's date]).

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