Is BBS4 p.Pro498fs (c.1493del) pathogenic?

BBS4 p.Pro498fs (c.1493del) is classified Uncertain significance in BBS4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-12). Very rare (popmax 0.00882%, nfe); Associated with Bardet-Biedl syndrome 4.

What condition is associated with BBS4 p.Pro498fs (c.1493del)?

BBS4 p.Pro498fs (c.1493del) is associated with Bardet-Biedl syndrome 4, Bardet-Biedl syndrome (ClinVar).

How common is BBS4 p.Pro498fs (c.1493del) in the general population?

BBS4 p.Pro498fs (c.1493del) is very rare (popmax 0.00882%, 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.Pro498fs

c.1493del · rs777455492 · VCV1027267

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00882%, nfe)

Conditions

Bardet-Biedl syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (16 of 16) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.37	GERP -2.6, phastCons 0.2
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00882% European (non-Finnish) · 104/1,179,678 alleles

Filtering AF 0.00741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00692%

Overall 0.00663% 107/1,613,088 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00882%	11,343
Remaining individualsnot grpmax-eligible	0.0032%	31,231
Finnishnot grpmax-eligible	0.00156%	64,000

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.Pro498fs
Coding: c.1493del
MANE Select: NM_033028
dbSNP: rs777455492
Type: Deletion
Location: chr15:72737519 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 498: 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 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bardet-Biedl syndrome

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.Pro498His Uncertain significance ★★ same residue
BBS4 p.Pro498= Likely benign ★ same residue
BBS4 c.1064_1106+97del Pathogenic/Likely pathogenic ★★ same condition
BBS4 p.Ala467fs Likely pathogenic ★★ same condition
BBS4 p.Glu432fs Pathogenic/Likely pathogenic ★★ same condition
BBS4 p.Leu114fs Pathogenic/Likely pathogenic ★★ same condition
BBS4 p.Leu310fs Pathogenic/Likely pathogenic ★★ same condition
BBS4 p.Leu381fs 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/bbs4-p-pro498fs (accessed [today's date]).

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