Is ARFGAP3 p.Ser458Leu (c.1373C>T) pathogenic?

ARFGAP3 p.Ser458Leu (c.1373C>T) is classified Uncertain significance in ARFGAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-11). AlphaMissense: likely pathogenic (0.8103); Ultra-rare (popmax 0.0111%, eas).

How common is ARFGAP3 p.Ser458Leu (c.1373C>T) in the general population?

ARFGAP3 p.Ser458Leu (c.1373C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about ARFGAP3 p.Ser458Leu (c.1373C>T)?

AlphaMissense predicts likely pathogenic (score 0.8103) — an in-silico prediction, not a clinical call.

ARFGAP3 p.Ser458Leu

c.1373C>T · rs776224296 · VCV2396470

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8103 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8103	likely pathogenic
REVEL	0.484	indeterminate
SaProt	LLR -13.23	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 1.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.79 · regional, not allelic
Overall
CADD	28.5	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 0.0111% East Asian · 5/44,892 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00112% 18/1,612,710 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,978
Remaining individualsnot grpmax-eligible	0.0016%	62,454
South Asian	0.0011%	90,700
European (non-Finnish)	0.000933%	107,229

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.Ser458Leu
Coding: c.1373C>T
MANE Select: NM_014570
dbSNP: rs776224296
Type: single nucleotide variant
Location: chr22:42807111 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.12 · 1 PDB
Residue 458: a modified residue (phosphoserine)

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

Similar variants

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
ARFGAP3 p.Arg15Cys 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-ser458leu (accessed [today's date]).

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