Is ARFGAP3 p.Arg404Ser (c.1210C>A) pathogenic?

ARFGAP3 p.Arg404Ser (c.1210C>A) is classified Uncertain significance in ARFGAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: ambiguous (0.5244); Very rare (popmax 0.00335%, amr).

How common is ARFGAP3 p.Arg404Ser (c.1210C>A) in the general population?

ARFGAP3 p.Arg404Ser (c.1210C>A) is very rare (popmax 0.00335%, amr) (gnomAD).

What do computational predictors say about ARFGAP3 p.Arg404Ser (c.1210C>A)?

AlphaMissense predicts ambiguous (score 0.5244) — an in-silico prediction, not a clinical call.

ARFGAP3 p.Arg404Ser

c.1210C>A · VCV3936691

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5244 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00335%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5244	ambiguous
REVEL	0.114	moderately benign-leaning
SaProt	LLR -6.23	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
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	23.2	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 0.00335% Admixed American · 2/59,654 alleles

Filtering AF 0.000765% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000606%

Overall 0.00124% 20/1,609,890 alleles · very rare exomes 16/1,457,746 · genomes 4/152,144 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00335%	29,827
East Asian	0.00223%	44,768
Remaining individualsnot grpmax-eligible	0.0016%	62,312
African / African-American	0.00134%	74,832
European (non-Finnish)	0.00127%	78,510

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.Arg404Ser
Coding: c.1210C>A
MANE Select: NM_014570
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.Arg404Cys Uncertain significance ★ ⚠ same residue
ARFGAP3 p.Arg404Gly 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-arg404ser (accessed [today's date]).

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