Is VPS33B p.Pro448Ser (c.1342C>T) pathogenic?

VPS33B p.Pro448Ser (c.1342C>T) is classified Uncertain significance in VPS33B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-06). AlphaMissense: likely benign (0.0669); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with VPS33B p.Pro448Ser (c.1342C>T)?

VPS33B p.Pro448Ser (c.1342C>T) is associated with Inborn genetic diseases (ClinVar).

How common is VPS33B p.Pro448Ser (c.1342C>T) in the general population?

VPS33B p.Pro448Ser (c.1342C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about VPS33B p.Pro448Ser (c.1342C>T)?

AlphaMissense predicts likely benign (score 0.0669) — an in-silico prediction, not a clinical call.

VPS33B p.Pro448Ser

c.1342C>T · rs2040455953 · VCV3188901

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0669	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -3.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 23 kb · p 0.036 · regional, not allelic
Overall
CADD	19.97	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0022% South Asian · 2/91,080 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,614,164 alleles · very rare exomes 2/1,461,872 · genomes 0/152,292 · joint denominator

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.Pro448Ser
Coding: c.1342C>T
MANE Select: NM_018668
dbSNP: rs2040455953
Type: single nucleotide variant
Location: chr15:91002113 (GRCh38)
Gene constraint: LOEUF 0.971 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.82

Full VPS33B 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

VPS33B c.1225+5G>C Pathogenic/Likely pathogenic ★★ same condition
VPS33B p.Arg171His Uncertain significance ★★ same condition
VPS33B p.Arg256Cys Uncertain significance ★★ ⚠ same condition
VPS33B p.Arg256His Uncertain significance ★★ ⚠ same condition
VPS33B p.Arg290Gln Uncertain significance ★★ ⚠ same condition
VPS33B p.Arg290Trp Uncertain significance ★★ ⚠ same condition
VPS33B p.Arg314His Uncertain significance ★★ ⚠ same condition
VPS33B p.Arg339Cys Uncertain significance ★★ ⚠ 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-pro448ser (accessed [today's date]).

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