Is RAB39B p.Ser153Pro (c.457T>C) pathogenic?

RAB39B p.Ser153Pro (c.457T>C) is classified Uncertain significance in RAB39B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely pathogenic (0.9983); Absent from gnomAD v4.1; Associated with early-onset parkinsonism-intellectual disability syndrome.

What condition is associated with RAB39B p.Ser153Pro (c.457T>C)?

RAB39B p.Ser153Pro (c.457T>C) is associated with early-onset parkinsonism-intellectual disability syndrome (ClinVar).

How common is RAB39B p.Ser153Pro (c.457T>C) in the general population?

RAB39B p.Ser153Pro (c.457T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RAB39B p.Ser153Pro (c.457T>C)?

AlphaMissense predicts likely pathogenic (score 0.9983) — an in-silico prediction, not a clinical call.

RAB39B p.Ser153Pro

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.457T>C · VCV4855821

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9983 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

early-onset parkinsonism-intellectual disability syndrome

Computational evidence

Protein change
AlphaMissense	0.9983	likely pathogenic · top 3% in RAB39B
REVEL	0.968	strongly pathogenic-leaning
SaProt	LLR -16.73	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 3,482 bp · p 2.9e-15 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RAB39B
Protein: p.Ser153Pro
Coding: c.457T>C
MANE Select: NM_171998
Type: single nucleotide variant
Location: chrX:155260988 (GRCh38)
Structure: AlphaFold pLDDT 88.67 · 1 PDB
Residue 153: a β-strand

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

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

Inheritance: X-linked recessive
Onset: Infancy

Similar variants

RAB39B p.Thr129Ile Uncertain significance ★★ ⚠ same condition
RAB39B p.Gly192Arg Pathogenic ★ ⚠ same condition
RAB39B p.Thr168Lys Pathogenic ★ same condition
RAB39B c.215+3G>A Conflicting classifications of pathogenicity ★ same condition
RAB39B p.Arg135fs Uncertain significance ★ same condition
RAB39B p.Gly178Arg Uncertain significance ★★ ⚠ same type
RAB39B p.Ser96Phe Uncertain significance ★★ ⚠ same type
RAB39B c.*1347C>T Benign ★★ 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/rab39b-p-ser153pro (accessed [today's date]).

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