Is RAB33B p.Phe122Ser (c.365T>C) pathogenic?

RAB33B p.Phe122Ser (c.365T>C) is classified Conflicting classifications of pathogenicity in RAB33B (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-02-16). AlphaMissense: likely pathogenic (0.9984); Absent from gnomAD v4.1; Associated with Smith-McCort dysplasia 2.

What condition is associated with RAB33B p.Phe122Ser (c.365T>C)?

RAB33B p.Phe122Ser (c.365T>C) is associated with Smith-McCort dysplasia 2 (ClinVar).

How common is RAB33B p.Phe122Ser (c.365T>C) in the general population?

RAB33B p.Phe122Ser (c.365T>C) is absent from gnomAD v4.1 (gnomAD).

How is Smith-McCort dysplasia inherited?

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

What do computational predictors say about RAB33B p.Phe122Ser (c.365T>C)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

RAB33B p.Phe122Ser

c.365T>C · rs1085307129 · VCV425561

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Smith-McCort dysplasia 2

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic · top 4% in RAB33B
REVEL	0.946	strongly pathogenic-leaning
SaProt	LLR -16.17	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 7.9	phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.022 · regional, not allelic
Overall
CADD	31.0	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

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: RAB33B
Protein: p.Phe122Ser
Coding: c.365T>C
MANE Select: NM_031296
dbSNP: rs1085307129
Type: single nucleotide variant
Location: chr4:139472801 (GRCh38)
Gene constraint: LOEUF 0.774 · pLI 0.39 (gnomAD)
Structure: AlphaFold pLDDT 81.55 · 2 PDB
Residue 122: an α-helix

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

Disease context

Smith-McCort dysplasia 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Smith-McCort dysplasia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

RAB33B p.Gln134Ter Pathogenic ★★ same condition
RAB33B c.*2355T>A Uncertain significance ★★ same condition
RAB33B p.Asn139Lys Uncertain significance ★★ ⚠ same condition
RAB33B p.Asn185Asp Uncertain significance ★★ ⚠ same condition
RAB33B p.Asn43Ser Uncertain significance ★★ ⚠ same condition
RAB33B c.*1303C>T Benign ★★ same condition
RAB33B c.*1403C>A Likely benign ★★ same condition
RAB33B c.*1751G>T Likely benign ★★ 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-phe122ser (accessed [today's date]).

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