Is RAB39B p.Arg135fs (c.402_403del) pathogenic?

RAB39B p.Arg135fs (c.402403del) is classified Uncertain significance in RAB39B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-01). Associated with early-onset parkinsonism-intellectual disability syndrome.

RAB39B p.Arg135fs

Q: What condition is associated with RAB39B p.Arg135fs (c.402_403del)?

RAB39B p.Arg135fs (c.402_403del) is associated with early-onset parkinsonism-intellectual disability syndrome, intellectual disability, X-linked 72 (ClinVar).

Q: How is Early-onset parkinsonism-intellectual disability syndrome inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.402_403del · VCV3775166

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

early-onset parkinsonism-intellectual disability syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: RAB39B
Protein: p.Arg135fs
Coding: c.402_403del
MANE Select: NM_171998
Type: Deletion
Location: chrX:155261042 (GRCh38)
Structure: AlphaFold pLDDT 88.67 · 1 PDB
Residue 135: an α-helix

Full RAB39B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

early-onset parkinsonism-intellectual disability syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability, X-linked 72

For Early-onset parkinsonism-intellectual disability syndrome (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy

Similar variants

RAB39B p.Ser96Phe Uncertain significance ★★ ⚠ same condition
RAB39B p.Thr129Ile Uncertain significance ★★ ⚠ same condition
RAB39B c.*1347C>T Benign ★★ same condition
RAB39B c.*1656= Benign ★★ same condition
RAB39B p.Thr181= Benign/Likely benign ★★ same condition
RAB39B p.Ala144del Likely pathogenic ★ same condition
RAB39B p.Glu187Ter Pathogenic ★ same condition
RAB39B p.Gly192Arg 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/rab39b-p-arg135fs (accessed [today's date]).

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