Is VPS13B p.Phe2268fs (c.6804del) pathogenic?

VPS13B p.Phe2268fs (c.6804del) is classified Pathogenic in VPS13B (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-06-14). Very rare (popmax 0.00549%, sas); Associated with Cohen syndrome.

What condition is associated with VPS13B p.Phe2268fs (c.6804del)?

VPS13B p.Phe2268fs (c.6804del) is associated with Cohen syndrome, congenital nervous system disorder (ClinVar).

How common is VPS13B p.Phe2268fs (c.6804del) in the general population?

VPS13B p.Phe2268fs (c.6804del) is very rare (popmax 0.00549%, sas) (gnomAD).

VPS13B p.Phe2268fs

c.6804del · rs761736983 · VCV817631

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Conditions

Cohen syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 38 of 62
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.1	GERP -3.7

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,082 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00031% 5/1,614,090 alleles · very rare exomes 5/1,461,734 · genomes 0/152,356 · 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.Phe2268fs
Coding: c.6804del
MANE Select: NM_152564
dbSNP: rs761736983
Type: Deletion
Location: chr8:99720489 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Residue 2268: 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); a UniProt-annotated variant site (in coh1; accelerates differentiation of adipose cells; response to insulin is abnormal)

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

Also linked: congenital nervous system disorder

Similar variants

VPS13B p.Ala2763fs Pathogenic ★★ same condition
VPS13B p.Ala3695fs Pathogenic/Likely pathogenic ★★ same condition
VPS13B p.Arg1779fs Pathogenic/Likely pathogenic ★★ same condition
VPS13B p.Arg2326_Ile2327insTer Pathogenic/Likely pathogenic ★★ same condition
VPS13B p.Arg3840fs Pathogenic/Likely pathogenic ★★ same condition
VPS13B p.Asn2406fs Pathogenic/Likely pathogenic ★★ same condition
VPS13B p.Asp306fs Pathogenic/Likely pathogenic ★★ same condition
VPS13B p.Asp3746fs 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-phe2268fs (accessed [today's date]).

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