Is VPS33B p.Pro191Ser (c.571C>T) pathogenic?

VPS33B p.Pro191Ser (c.571C>T) is classified Uncertain significance in VPS33B (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-15). AlphaMissense: likely benign (0.0982); Ultra-rare (popmax 0.0134%, eas).

How common is VPS33B p.Pro191Ser (c.571C>T) in the general population?

VPS33B p.Pro191Ser (c.571C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about VPS33B p.Pro191Ser (c.571C>T)?

AlphaMissense predicts likely benign (score 0.0982) — an in-silico prediction, not a clinical call.

VPS33B p.Pro191Ser

c.571C>T · rs775778438 · VCV2176521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0982 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0982	likely benign
REVEL	0.283	benign-leaning
SaProt	LLR -9.41	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 4.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 23 kb · p 0.036 · regional, not allelic
Overall
CADD	16.08	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 0.0134% East Asian · 6/44,882 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000558% 9/1,614,216 alleles · ultra-rare exomes 9/1,461,888 · genomes 0/152,328 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,480
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	0.000169%	590,019

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.Pro191Ser
Coding: c.571C>T
MANE Select: NM_018668
dbSNP: rs775778438
Type: single nucleotide variant
Location: chr15:91007501 (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

Similar variants

VPS33B p.Pro191Arg Uncertain significance ★ ⚠ same residue
VPS33B c.1030+1G>A Likely pathogenic ★★ same type
VPS33B c.1225+5G>C Pathogenic/Likely pathogenic ★★ same type
VPS33B c.239+5G>A Pathogenic/Likely pathogenic ★★ same type
VPS33B c.240-1G>C Pathogenic/Likely pathogenic ★★ same type
VPS33B c.403+2T>A Pathogenic ★★ same type
VPS33B p.Arg107Ter Pathogenic/Likely pathogenic ★★ same type
VPS33B p.Arg416Ter Pathogenic ★★ same type

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-pro191ser (accessed [today's date]).

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