Is VPS33B p.Ala2Val (c.5C>T) pathogenic?

VPS33B p.Ala2Val (c.5C>T) is classified Uncertain significance in VPS33B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely benign (0.3136); Very rare (popmax 0.000347%, nfe).

How common is VPS33B p.Ala2Val (c.5C>T) in the general population?

VPS33B p.Ala2Val (c.5C>T) is very rare (popmax 0.000347%, nfe) (gnomAD).

What do computational predictors say about VPS33B p.Ala2Val (c.5C>T)?

AlphaMissense predicts likely benign (score 0.3136) — an in-silico prediction, not a clinical call.

VPS33B p.Ala2Val

c.5C>T · rs1029244647 · VCV3002945

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3136 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000347%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3136	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -8.86	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 9.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 23 kb · p 0.036 · regional, not allelic
Overall
CADD	28.6	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 0.000347% European (non-Finnish) · 4/1,151,584 alleles

Filtering AF 8.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.000255% 4/1,568,018 alleles · very rare exomes 4/1,415,698 · genomes 0/152,320 · 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.Ala2Val
Coding: c.5C>T
MANE Select: NM_018668
dbSNP: rs1029244647
Type: single nucleotide variant
Location: chr15:91022245 (GRCh38)
Gene constraint: LOEUF 0.971 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.82
Residue 2: a modified residue (n-acetylalanine)

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

Similar variants

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
VPS33B p.Arg438Ter 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-ala2val (accessed [today's date]).

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