Is RAB33B p.Ser154Arg (c.462T>A) pathogenic?

RAB33B p.Ser154Arg (c.462T>A) is classified Uncertain significance in RAB33B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-20). AlphaMissense: ambiguous (0.3786); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with RAB33B p.Ser154Arg (c.462T>A)?

RAB33B p.Ser154Arg (c.462T>A) is associated with Inborn genetic diseases (ClinVar).

How common is RAB33B p.Ser154Arg (c.462T>A) in the general population?

RAB33B p.Ser154Arg (c.462T>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about RAB33B p.Ser154Arg (c.462T>A)?

AlphaMissense predicts ambiguous (score 0.3786) — an in-silico prediction, not a clinical call.

RAB33B p.Ser154Arg

c.462T>A · rs763510197 · VCV1516088

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3786	ambiguous
REVEL	0.247	benign-leaning
SaProt	LLR -9.16	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.47	phastCons 0.12
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.022 · regional, not allelic
Overall
CADD	17.11	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 0.004% African / African-American · 3/75,030 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000494%

Overall 0.000274% 4/1,461,862 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,010
Admixed American	0.00167%	60,018

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: RAB33B
Protein: p.Ser154Arg
Coding: c.462T>A
MANE Select: NM_031296
dbSNP: rs763510197
Type: single nucleotide variant
Location: chr4:139472898 (GRCh38)
Gene constraint: LOEUF 0.774 · pLI 0.39 (gnomAD)
Structure: AlphaFold pLDDT 81.55 · 2 PDB
Residue 154: an α-helix

Full RAB33B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RAB33B p.Ile191Met Uncertain significance ★★ ⚠ same condition
RAB33B p.Leu49Val Uncertain significance ★★ ⚠ same condition
RAB33B p.Val113Met Uncertain significance ★★ ⚠ same condition
RAB33B p.Arg143Trp Uncertain significance ★ ⚠ same condition
RAB33B p.Arg32Cys Uncertain significance ★ ⚠ same condition
RAB33B p.Arg57Cys Uncertain significance ★ ⚠ same condition
RAB33B p.Arg57Leu Uncertain significance ★ ⚠ same condition
RAB33B p.Asn139Ser Conflicting classifications of pathogenicity ★ ⚠ 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/rab33b-p-ser154arg (accessed [today's date]).

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