Is RAB33B p.Phe112= (c.336C>T) pathogenic?

RAB33B p.Phe112= (c.336C>T) is classified Conflicting classifications of pathogenicity in RAB33B (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-07). Ultra-rare (popmax 0.0856%, sas); Associated with Smith-McCort dysplasia 2.

What condition is associated with RAB33B p.Phe112= (c.336C>T)?

RAB33B p.Phe112= (c.336C>T) is associated with Smith-McCort dysplasia 2 (ClinVar).

How common is RAB33B p.Phe112= (c.336C>T) in the general population?

RAB33B p.Phe112= (c.336C>T) is ultra-rare (popmax 0.0856%, sas) (gnomAD).

How is Smith-McCort dysplasia inherited?

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

RAB33B p.Phe112=

c.336C>T · rs142541603 · VCV347564

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0856%, sas)

Conditions

Smith-McCort dysplasia 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9
Overall
CADD	10.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0856% South Asian · 78/91,076 alleles

Filtering AF 0.0703% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0646%

Overall 0.0275% 444/1,613,970 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0856%	1,168
Remaining individualsnot grpmax-eligible	0.032%	3,125
European (non-Finnish)	0.0288%	3,470
African / African-American	0.008%	12,506

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.Phe112=
Coding: c.336C>T
MANE Select: NM_031296
dbSNP: rs142541603
Type: single nucleotide variant
Location: chr4:139472772 (GRCh38)
Gene constraint: LOEUF 0.774 · pLI 0.39 (gnomAD)
Structure: AlphaFold pLDDT 81.55 · 2 PDB
Residue 112: a β-strand

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-phe112 (accessed [today's date]).

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