Is VPS13B p.Pro2000Ser (c.5998C>T) pathogenic?

VPS13B p.Pro2000Ser (c.5998C>T) is classified Uncertain significance in VPS13B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-20). AlphaMissense: ambiguous (0.4303); Absent from gnomAD v4.1; Associated with Cohen syndrome.

What condition is associated with VPS13B p.Pro2000Ser (c.5998C>T)?

VPS13B p.Pro2000Ser (c.5998C>T) is associated with Cohen syndrome (ClinVar).

How common is VPS13B p.Pro2000Ser (c.5998C>T) in the general population?

VPS13B p.Pro2000Ser (c.5998C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VPS13B p.Pro2000Ser (c.5998C>T)?

AlphaMissense predicts ambiguous (score 0.4303) — an in-silico prediction, not a clinical call.

VPS13B p.Pro2000Ser

c.5998C>T · rs939700991 · VCV859247

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4303 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Cohen syndrome

Computational evidence

Protein change
AlphaMissense	0.4303	ambiguous
REVEL	0.547	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 760 kb · p 0.015 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P2025S vs ClinVar P2000S) — verify the residue.

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: VPS13B
Protein: p.Pro2000Ser
Coding: c.5998C>T
MANE Select: NM_152564
dbSNP: rs939700991
Type: single nucleotide variant
Location: chr8:99661443 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)

Full VPS13B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cohen syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VPS13B c.10867+1G>A Likely pathogenic ★★ same condition
VPS13B c.10868-2A>G Likely pathogenic ★★ same condition
VPS13B c.11044+1G>A Pathogenic/Likely pathogenic ★★ same condition
VPS13B c.11392+1G>T Likely pathogenic ★★ same condition
VPS13B c.11496-2A>G Pathogenic ★★ same condition
VPS13B c.11746-1G>A Pathogenic/Likely pathogenic ★★ same condition
VPS13B c.1843+1G>A Likely pathogenic ★★ same condition
VPS13B c.2516-2A>G Likely pathogenic ★★ 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/vps13b-p-pro2000ser (accessed [today's date]).

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