Is ARFGAP3 p.Arg15Cys (c.43C>T) pathogenic?

ARFGAP3 p.Arg15Cys (c.43C>T) is classified Uncertain significance in ARFGAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). AlphaMissense: likely pathogenic (0.6475); Very rare (popmax 0.00843%, amr).

How common is ARFGAP3 p.Arg15Cys (c.43C>T) in the general population?

ARFGAP3 p.Arg15Cys (c.43C>T) is very rare (popmax 0.00843%, amr) (gnomAD).

What do computational predictors say about ARFGAP3 p.Arg15Cys (c.43C>T)?

AlphaMissense predicts likely pathogenic (score 0.6475) — an in-silico prediction, not a clinical call.

ARFGAP3 p.Arg15Cys

c.43C>T · rs1419390626 · VCV3128349

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6475 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00843%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6475	likely pathogenic
REVEL	0.477	indeterminate
SaProt	LLR -11.99	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP -1.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.79 · regional, not allelic
Overall
CADD	29.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00843% Admixed American · 4/47,458 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00172%

Overall 0.000367% 5/1,363,852 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00843%	11,864
European (non-Finnish)	8.85e-05%	1,130,141

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: ARFGAP3
Protein: p.Arg15Cys
Coding: c.43C>T
MANE Select: NM_014570
dbSNP: rs1419390626
Type: single nucleotide variant
Location: chr22:42857140 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.12 · 1 PDB
Residue 15: the arf-gap domain; an α-helix

Full ARFGAP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARFGAP3 p.Arg15His Uncertain significance ★ ⚠ same residue
ARFGAP3 p.Ala164Val Uncertain significance ★ ⚠ same type
ARFGAP3 p.Ala170Glu Uncertain significance ★ ⚠ same type
ARFGAP3 p.Ala234Thr Uncertain significance ★ ⚠ same type
ARFGAP3 p.Ala238Gly Uncertain significance ★ ⚠ same type
ARFGAP3 p.Ala262Thr Uncertain significance ★ ⚠ same type
ARFGAP3 p.Ala335Thr Uncertain significance ★ ⚠ same type
ARFGAP3 p.Ala426Ser 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/arfgap3-p-arg15cys (accessed [today's date]).

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