Is ARFGAP3 p.Arg404Cys (c.1210C>T) pathogenic?

ARFGAP3 p.Arg404Cys (c.1210C>T) is classified Uncertain significance in ARFGAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely benign (0.1373); Ultra-rare (popmax 0.0667%, afr).

How common is ARFGAP3 p.Arg404Cys (c.1210C>T) in the general population?

ARFGAP3 p.Arg404Cys (c.1210C>T) is ultra-rare (popmax 0.0667%, afr) (gnomAD).

What do computational predictors say about ARFGAP3 p.Arg404Cys (c.1210C>T)?

AlphaMissense predicts likely benign (score 0.1373) — an in-silico prediction, not a clinical call.

ARFGAP3 p.Arg404Cys

c.1210C>T · rs150358440 · VCV2594985

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1373 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1373	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -9.57	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 5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.79 · regional, not allelic
Overall
CADD	25.3	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0667% African / African-American · 50/74,954 alleles

Filtering AF 0.0519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0467%

Overall 0.00584% 94/1,610,008 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0667%	1,499
Admixed American	0.0134%	7,459
South Asian	0.0111%	9,025
East Asian	0.0067%	14,919
Remaining individualsnot grpmax-eligible	0.00321%	31,167
European (non-Finnish)	0.00178%	56,078

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.Arg404Cys
Coding: c.1210C>T
MANE Select: NM_014570
dbSNP: rs150358440
Type: single nucleotide variant
Location: chr22:42808877 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.12 · 1 PDB
Residue 404: the 'disordered' region

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

Similar variants

ARFGAP3 p.Arg404Gly Uncertain significance ★ ⚠ same residue
ARFGAP3 p.Arg404Ser 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

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-arg404cys (accessed [today's date]).

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