Is VPS4B p.Phe232Ser (c.695T>C) pathogenic?

VPS4B p.Phe232Ser (c.695T>C) is classified Uncertain significance in VPS4B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-05). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1.

How common is VPS4B p.Phe232Ser (c.695T>C) in the general population?

VPS4B p.Phe232Ser (c.695T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VPS4B p.Phe232Ser (c.695T>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

VPS4B p.Phe232Ser

c.695T>C · rs1915778177 · VCV2533509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 3% in VPS4B
REVEL	0.982	strongly pathogenic-leaning
SaProt	LLR -14.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 3,449 bp · p 5.2e-12 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: VPS4B
Protein: p.Phe232Ser
Coding: c.695T>C
MANE Select: NM_004869
dbSNP: rs1915778177
Type: single nucleotide variant
Location: chr18:63400143 (GRCh38)
Gene constraint: LOEUF 0.548 · pLI 0.82 (gnomAD)
Structure: AlphaFold pLDDT 86.31 · 7 PDB
Residue 232: a β-strand

Full VPS4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

VPS4B p.Ala123Val Uncertain significance ★ ⚠ same type
VPS4B p.Ala24Ser Uncertain significance ★ ⚠ same type
VPS4B p.Ala251Thr Uncertain significance ★ ⚠ same type
VPS4B p.Ala305Val Uncertain significance ★ ⚠ same type
VPS4B p.Ala307Thr Uncertain significance ★ ⚠ same type
VPS4B p.Ala95Val Uncertain significance ★ ⚠ same type
VPS4B p.Arg128Gln Uncertain significance ★ ⚠ same type
VPS4B p.Arg252Cys Uncertain significance ★ ⚠ 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/vps4b-p-phe232ser (accessed [today's date]).

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