Is ARFGEF1 p.Val1663Ile (c.4987G>A) pathogenic?

ARFGEF1 p.Val1663Ile (c.4987G>A) is classified Uncertain significance in ARFGEF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-17). AlphaMissense: likely benign (0.0828); Very rare (popmax 0.00439%, sas); Associated with developmental delay, impaired speech, and behavioral abnormalities, with or without seizures.

How common is ARFGEF1 p.Val1663Ile (c.4987G>A) in the general population?

ARFGEF1 p.Val1663Ile (c.4987G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about ARFGEF1 p.Val1663Ile (c.4987G>A)?

AlphaMissense predicts likely benign (score 0.0828) — an in-silico prediction, not a clinical call.

ARFGEF1 p.Val1663Ile

Q: What condition is associated with ARFGEF1 p.Val1663Ile (c.4987G>A)?

ARFGEF1 p.Val1663Ile (c.4987G>A) is associated with developmental delay, impaired speech, and behavioral abnormalities, with or without seizures (ClinVar).

c.4987G>A · VCV4078007

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0828 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental delay, impaired speech, and behavioral abnormalities, with or without seizures

Computational evidence

Protein change
AlphaMissense	0.0828	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -6.75	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 3.4	GERP -0.16, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 5,879 bp · p 2.1e-13 · regional, not allelic
Overall
CADD	22.6	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 0.00439% South Asian · 4/91,076 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00041% 6/1,461,820 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,769
European (non-Finnish)	0.000169%	589,995

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: ARFGEF1
Protein: p.Val1663Ile
Coding: c.4987G>A
MANE Select: NM_006421
Type: single nucleotide variant
Location: chr8:67203224 (GRCh38)
Gene constraint: LOEUF 0.236 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.23 · 3 PDB
Residue 1663: a UniProt-annotated variant site (in dedisb; decreased protein abundance); a UniProt-annotated variant site (in dedisb)

Full ARFGEF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental delay, impaired speech, and behavioral abnormalities, with or without seizures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARFGEF1 p.Arg1272Ter Pathogenic ★★ same condition
ARFGEF1 p.Arg1543Ter Pathogenic ★★ same condition
ARFGEF1 p.Arg1774Ter Pathogenic ★★ same condition
ARFGEF1 p.Asp798Asn Pathogenic/Likely pathogenic ★★ same condition
ARFGEF1 c.2699-3C>T Uncertain significance ★★ same condition
ARFGEF1 p.Asn373Ser Uncertain significance ★★ ⚠ same condition
ARFGEF1 p.Ile481Leu Uncertain significance ★★ ⚠ same condition
ARFGEF1 p.Phe1796Leu Uncertain significance ★★ ⚠ 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/arfgef1-p-val1663ile (accessed [today's date]).

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