Is ARL2 p.Lys9Arg (c.26A>G) pathogenic?

ARL2 p.Lys9Arg (c.26A>G) is classified Uncertain significance in ARL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). AlphaMissense: likely benign (0.1851); Ultra-rare (popmax 0.0167%, mid).

How common is ARL2 p.Lys9Arg (c.26A>G) in the general population?

ARL2 p.Lys9Arg (c.26A>G) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about ARL2 p.Lys9Arg (c.26A>G)?

AlphaMissense predicts likely benign (score 0.1851) — an in-silico prediction, not a clinical call.

ARL2 p.Lys9Arg

c.26A>G · VCV3785431

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1851 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1851	likely benign
REVEL	0.336	indeterminate
SaProt	LLR -6.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 7,644 bp · p 0.081 · regional, not allelic
Overall
CADD	28.7	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 0.0167% Middle Eastern · 1/5,984 alleles

Filtering AF 0.00391% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00357%

Overall 0.00413% 65/1,574,698 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,984
Admixed American	0.00548%	18,262
European (non-Finnish)	0.00498%	20,073
Remaining individualsnot grpmax-eligible	0.00494%	20,256

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: ARL2
Protein: p.Lys9Arg
Coding: c.26A>G
MANE Select: NM_001667
Type: single nucleotide variant
Location: chr11:65014233 (GRCh38)
Gene constraint: LOEUF 0.935 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 94.31 · 8 PDB
Residue 9: an α-helix

Full ARL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARL2 p.Arg139His Uncertain significance ★ ⚠ same type
ARL2 p.Arg148Cys Uncertain significance ★ ⚠ same type
ARL2 p.Arg148His Uncertain significance ★ ⚠ same type
ARL2 p.Arg179Cys Uncertain significance ★ ⚠ same type
ARL2 p.Arg179His Uncertain significance ★ ⚠ same type
ARL2 p.Arg74Gln Uncertain significance ★ ⚠ same type
ARL2 p.Arg98His Uncertain significance ★ ⚠ same type
ARL2 p.Asp128Glu 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/arl2-p-lys9arg (accessed [today's date]).

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