Is ARL2 p.Leu165Val (c.493C>G) pathogenic?

ARL2 p.Leu165Val (c.493C>G) is classified Uncertain significance in ARL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). AlphaMissense: likely benign (0.2117); Ultra-rare (popmax 0.0312%, eas).

How common is ARL2 p.Leu165Val (c.493C>G) in the general population?

ARL2 p.Leu165Val (c.493C>G) is ultra-rare (popmax 0.0312%, eas) (gnomAD).

What do computational predictors say about ARL2 p.Leu165Val (c.493C>G)?

AlphaMissense predicts likely benign (score 0.2117) — an in-silico prediction, not a clinical call.

ARL2 p.Leu165Val

c.493C>G · VCV3430153

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2117 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2117	likely benign
REVEL	0.673	pathogenic-leaning
SaProt	LLR -10.54	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.64, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 7,644 bp · p 0.081 · regional, not allelic
Overall
CADD	23.9	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 0.0312% East Asian · 14/44,904 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.0013% 21/1,613,358 alleles · ultra-rare exomes 20/1,461,152 · genomes 1/152,206 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0312%	3,207
Remaining individualsnot grpmax-eligible	0.0064%	15,619
Admixed American	0.00167%	59,996
European (non-Finnish)	0.000169%	589,984

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.Leu165Val
Coding: c.493C>G
MANE Select: NM_001667
Type: single nucleotide variant
Location: chr11:65021793 (GRCh38)
Gene constraint: LOEUF 0.935 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 94.31 · 8 PDB
Residue 165: an α-helix

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

Similar variants

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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-leu165val (accessed [today's date]).

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