Is VPS33B p.Pro7Ser (c.19C>T) pathogenic?

VPS33B p.Pro7Ser (c.19C>T) is classified Uncertain significance in VPS33B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-19). AlphaMissense: likely benign (0.0848); Very rare (popmax 0.00803%, sas); Associated with Inborn genetic diseases.

What condition is associated with VPS33B p.Pro7Ser (c.19C>T)?

VPS33B p.Pro7Ser (c.19C>T) is associated with Inborn genetic diseases (ClinVar).

How common is VPS33B p.Pro7Ser (c.19C>T) in the general population?

VPS33B p.Pro7Ser (c.19C>T) is very rare (popmax 0.00803%, sas) (gnomAD).

What do computational predictors say about VPS33B p.Pro7Ser (c.19C>T)?

AlphaMissense predicts likely benign (score 0.0848) — an in-silico prediction, not a clinical call.

VPS33B p.Pro7Ser

c.19C>T · rs1167676948 · VCV2539020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00803%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0848	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -5.31	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 6.3	GERP 0.53, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 23 kb · p 0.036 · regional, not allelic
Overall
CADD	19.62	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 0.00803% South Asian · 7/87,180 alleles

Filtering AF 0.00373% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00264%

Overall 0.000507% 8/1,578,576 alleles · very rare exomes 7/1,426,236 · genomes 1/152,340 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00803%	12,454
Remaining individualsnot grpmax-eligible	0.00164%	60,878

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.Pro7Ser
Coding: c.19C>T
MANE Select: NM_018668
dbSNP: rs1167676948
Type: single nucleotide variant
Location: chr15:91022231 (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-pro7ser (accessed [today's date]).

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