Is VPS33B p.Ser243Phe (c.728C>T) pathogenic?

VPS33B p.Ser243Phe (c.728C>T) is classified Uncertain significance in VPS33B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-09). AlphaMissense: likely pathogenic (0.9082); Ultra-rare (popmax 0.0107%, afr); Associated with keratoderma-ichthyosis-deafness syndrome, autosomal recessive.

What condition is associated with VPS33B p.Ser243Phe (c.728C>T)?

VPS33B p.Ser243Phe (c.728C>T) is associated with keratoderma-ichthyosis-deafness syndrome, autosomal recessive, arthrogryposis, renal dysfunction, and cholestasis 1, cholestasis, progressive familial intrahepatic, 12 (ClinVar).

How common is VPS33B p.Ser243Phe (c.728C>T) in the general population?

VPS33B p.Ser243Phe (c.728C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about VPS33B p.Ser243Phe (c.728C>T)?

AlphaMissense predicts likely pathogenic (score 0.9082) — an in-silico prediction, not a clinical call.

VPS33B p.Ser243Phe

c.728C>T · rs139829189 · VCV2691319

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9082 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

keratoderma-ichthyosis-deafness syndrome, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9082	likely pathogenic
REVEL	0.741	pathogenic-leaning
SaProt	LLR -12.97	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 23 kb · p 0.036 · regional, not allelic
Overall
CADD	29.6	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

Grpmax group 0.0107% African / African-American · 8/75,034 alleles

Filtering AF 0.00527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00062% 10/1,614,172 alleles · ultra-rare exomes 4/1,461,890 · genomes 6/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,379
Remaining individualsnot grpmax-eligible	0.0032%	31,255

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: VPS33B
Protein: p.Ser243Phe
Coding: c.728C>T
MANE Select: NM_018668
dbSNP: rs139829189
Type: single nucleotide variant
Location: chr15:91006702 (GRCh38)
Gene constraint: LOEUF 0.971 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.82
Residue 243: a UniProt-annotated variant site (in arcs1; no effect on interaction with vipas39; impairs localization to vipas39-containing endosomal compartment)

Full VPS33B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

keratoderma-ichthyosis-deafness syndrome, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arthrogryposis, renal dysfunction, and cholestasis 1 cholestasis, progressive familial intrahepatic, 12

Similar variants

VPS33B c.1030+1G>A Likely pathogenic ★★ same condition
VPS33B c.1225+5G>C Pathogenic/Likely pathogenic ★★ same condition
VPS33B c.239+5G>A Pathogenic/Likely pathogenic ★★ same condition
VPS33B c.240-1G>C Pathogenic/Likely pathogenic ★★ same condition
VPS33B c.403+2T>A Pathogenic ★★ same condition
VPS33B p.Arg107Ter Pathogenic/Likely pathogenic ★★ same condition
VPS33B p.Arg416Ter Pathogenic ★★ same condition
VPS33B p.Arg438Ter 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/vps33b-p-ser243phe (accessed [today's date]).

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