Is BBS4 p.Asp442fs (c.1323dup) pathogenic?

BBS4 p.Asp442fs (c.1323dup) is classified Pathogenic in BBS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). Very rare (popmax 8.47e-05%, nfe); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS4 p.Asp442fs (c.1323dup)?

BBS4 p.Asp442fs (c.1323dup) is associated with Bardet-Biedl syndrome (ClinVar).

How common is BBS4 p.Asp442fs (c.1323dup) in the general population?

BBS4 p.Asp442fs (c.1323dup) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Bardet-Biedl syndrome inherited?

Typically Autosomal recessive, Oligogenic (Orphanet). A genetic counselor can assess individual risk for a family.

BBS4 p.Asp442fs

c.1323dup · VCV4728489

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Bardet-Biedl 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 15 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.11	GERP -2.3, phastCons 0.001

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 6.84e-05% 1/1,461,888 alleles · very rare

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: BBS4
Protein: p.Asp442fs
Coding: c.1323dup
MANE Select: NM_033028
Type: Duplication
Location: chr15:72736833 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 442: the 'required for localization to centrosomes' region; the 'disordered' region

Full BBS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Bardet-Biedl syndrome (Orphanet):

Inheritance: Autosomal recessive, Oligogenic
Onset: Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Specific population)

Similar variants

BBS4 p.Asp442Gly Uncertain significance ★★ ⚠ same residue
BBS4 p.Ile172fs Pathogenic ★★ same condition
BBS4 p.Ser464fs Pathogenic/Likely pathogenic ★★ same condition
BBS4 p.Thr206fs Pathogenic/Likely pathogenic ★★ same condition
BBS4 c.332+27dup Benign/Likely benign ★★ same condition
BBS4 c.76+18dup Likely benign ★★ same condition
BBS4 p.Ala228fs Pathogenic ★ same condition
BBS4 p.Leu376fs 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/bbs4-p-asp442fs (accessed [today's date]).

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