Is VPS13B p.Pro1004= (c.3012C>T) pathogenic?

VPS13B p.Pro1004= (c.3012C>T) is classified Likely benign in VPS13B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-22). Very rare (popmax 8.48e-05%, nfe); Associated with Cohen syndrome.

What condition is associated with VPS13B p.Pro1004= (c.3012C>T)?

VPS13B p.Pro1004= (c.3012C>T) is associated with Cohen syndrome (ClinVar).

How common is VPS13B p.Pro1004= (c.3012C>T) in the general population?

VPS13B p.Pro1004= (c.3012C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

VPS13B p.Pro1004=

c.3012C>T · rs199519352 · VCV1619536

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Cohen syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -3.4
Overall
CADD	3.432	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,940 alleles

Overall 6.2e-05% 1/1,614,086 alleles · very rare exomes 0/1,461,794 · genomes 1/152,292 · 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: VPS13B
Protein: p.Pro1004=
Coding: c.3012C>T
MANE Select: NM_152564
dbSNP: rs199519352
Type: single nucleotide variant
Location: chr8:99391634 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Residue 1004: a UniProt-annotated variant site (in coh1); a UniProt-annotated variant site (in coh1; leads to an accumulation of liquid droplets and accelerates differentiation of adipose cells; response to insulin is abnormal); a UniProt-annotated variant site (in coh1; glycosylation is defective; accelerates differentiation of adipose cells)

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 p.Pro1004His Uncertain significance ★ same residue
VPS13B p.Pro1004Ser Uncertain significance ★ same residue
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

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-pro1004 (accessed [today's date]).

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