Is ARF1 p.Arg99His (c.296G>A) pathogenic?

ARF1 p.Arg99His (c.296G>A) is classified Pathogenic/Likely pathogenic in ARF1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-03-18). AlphaMissense: likely pathogenic (0.9937); Absent from gnomAD v4.1; Associated with periventricular nodular heterotopia 8.

What condition is associated with ARF1 p.Arg99His (c.296G>A)?

ARF1 p.Arg99His (c.296G>A) is associated with periventricular nodular heterotopia 8 (ClinVar).

How common is ARF1 p.Arg99His (c.296G>A) in the general population?

ARF1 p.Arg99His (c.296G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARF1 p.Arg99His (c.296G>A)?

AlphaMissense predicts likely pathogenic (score 0.9937) — an in-silico prediction, not a clinical call.

ARF1 p.Arg99His

c.296G>A · rs1558087712 · VCV590334

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9937 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,188)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

periventricular nodular heterotopia 8

Computational evidence

Protein change
AlphaMissense	0.9937	likely pathogenic ✓ concordant with ClinVar
REVEL	0.694	pathogenic-leaning
SaProt	LLR -13.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.77, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 582 bp · p 9.3e-16 · regional, not allelic
Overall
CADD	25.5	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

No allele count reported in gnomAD v4.1 (AN 1,614,188). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ARF1
Protein: p.Arg99His
Coding: c.296G>A
MANE Select: NM_001658
dbSNP: rs1558087712
Type: single nucleotide variant
Location: chr1:228097627 (GRCh38)
Gene constraint: LOEUF 0.247 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.93 · 40 PDB
Residue 99: an α-helix; a UniProt-annotated variant site (in pvnh8; uncertain significance)

Full ARF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

periventricular nodular heterotopia 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARF1 p.Arg99Cys Likely pathogenic ★ same residue
ARF1 p.Arg19Cys Likely pathogenic ★★ same condition
ARF1 p.Gly70Ser Likely pathogenic ★★ same condition
ARF1 p.Thr48Ile Likely pathogenic ★★ same condition
ARF1 p.Tyr35Asp Pathogenic/Likely pathogenic ★★ same condition
ARF1 p.Lys127Glu Pathogenic ★ same condition
ARF1 p.Phe51Leu Pathogenic ★ same condition
ARF1 p.Pro131Arg Pathogenic ★ 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/arf1-p-arg99his (accessed [today's date]).

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