Is ARL13B p.Met26Val (c.76A>G) pathogenic?

ARL13B p.Met26Val (c.76A>G) is classified Uncertain significance in ARL13B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-30). AlphaMissense: likely benign (0.3321); Very rare (popmax 0.000678%, nfe); Associated with Joubert syndrome 8.

What condition is associated with ARL13B p.Met26Val (c.76A>G)?

ARL13B p.Met26Val (c.76A>G) is associated with Joubert syndrome 8 (ClinVar).

How common is ARL13B p.Met26Val (c.76A>G) in the general population?

ARL13B p.Met26Val (c.76A>G) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about ARL13B p.Met26Val (c.76A>G)?

AlphaMissense predicts likely benign (score 0.3321) — an in-silico prediction, not a clinical call.

ARL13B p.Met26Val

c.76A>G · rs746717195 · VCV2042528

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3321 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Joubert syndrome 8

Computational evidence

Protein change
AlphaMissense	0.3321	likely benign
REVEL	0.383	indeterminate
SaProt	LLR -9.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
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 1.02	unconstrained · MANE · 73 kb · p 0.6 · regional, not allelic
Overall
CADD	23.8	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 0.000678% European (non-Finnish) · 8/1,179,100 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,612,400 alleles · very rare exomes 7/1,460,176 · genomes 1/152,224 · joint denominator

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: ARL13B
Protein: p.Met26Val
Coding: c.76A>G
MANE Select: NM_001174150
dbSNP: rs746717195
Type: single nucleotide variant
Location: chr3:93995890 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.92

Full ARL13B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Joubert syndrome 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARL13B c.1141+1G>A Likely pathogenic ★★ same condition
ARL13B c.131-1G>T Pathogenic/Likely pathogenic ★★ same condition
ARL13B p.Arg200Cys Pathogenic/Likely pathogenic ★★ same condition
ARL13B p.Cys287Ter Pathogenic/Likely pathogenic ★★ same condition
ARL13B p.Gln258Ter Pathogenic/Likely pathogenic ★★ same condition
ARL13B p.Gly75Arg Pathogenic ★★ same condition
ARL13B c.1211-1G>C Uncertain significance ★★ same condition
ARL13B p.Ala210Val 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/arl13b-p-met26val (accessed [today's date]).

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