Is VPS33B p.Ser271Pro (c.811T>C) pathogenic?

VPS33B p.Ser271Pro (c.811T>C) is classified Uncertain significance in VPS33B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-22). AlphaMissense: ambiguous (0.5621); Very rare (popmax 0.000593%, nfe); Associated with Inborn genetic diseases.

What condition is associated with VPS33B p.Ser271Pro (c.811T>C)?

VPS33B p.Ser271Pro (c.811T>C) is associated with Inborn genetic diseases (ClinVar).

How common is VPS33B p.Ser271Pro (c.811T>C) in the general population?

VPS33B p.Ser271Pro (c.811T>C) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about VPS33B p.Ser271Pro (c.811T>C)?

AlphaMissense predicts ambiguous (score 0.5621) — an in-silico prediction, not a clinical call.

VPS33B p.Ser271Pro

c.811T>C · rs2040605521 · VCV2487118

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5621	ambiguous
REVEL	0.356	indeterminate
SaProt	LLR -14.57	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 23 kb · p 0.036 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,180,036 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,614,202 alleles · very rare exomes 7/1,461,894 · genomes 0/152,308 · 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.Ser271Pro
Coding: c.811T>C
MANE Select: NM_018668
dbSNP: rs2040605521
Type: single nucleotide variant
Location: chr15:91006413 (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 p.Ser271= Likely benign ★ same residue
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

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-ser271pro (accessed [today's date]).

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