Is BBS4 p.Ile172fs (c.514dup) pathogenic?

BBS4 p.Ile172fs (c.514dup) is classified Pathogenic in BBS4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-08). Very rare (popmax 0.00167%, amr); Associated with Bardet-Biedl syndrome 4.

What condition is associated with BBS4 p.Ile172fs (c.514dup)?

BBS4 p.Ile172fs (c.514dup) is associated with Bardet-Biedl syndrome 4, Bardet-Biedl syndrome (ClinVar).

How common is BBS4 p.Ile172fs (c.514dup) in the general population?

BBS4 p.Ile172fs (c.514dup) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Bardet-Biedl syndrome inherited?

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

BBS4 p.Ile172fs

c.514dup · rs779047261 · VCV2200217

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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	predicted	premature termination codon in exon 8 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.52	GERP -0.41, phastCons 0.001
Overall
CADD	27.8	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 0.00167% Admixed American · 1/60,002 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00105% 17/1,613,992 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,467
Remaining individualsnot grpmax-eligible	0.0032%	31,242
Admixed Americangrpmax	0.00167%	60,002
European (non-Finnish)	0.000169%	590,002

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile172fs
Coding: c.514dup
MANE Select: NM_033028
dbSNP: rs779047261
Type: Duplication
Location: chr15:72724581 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 172: the 'interaction with pcm1' 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.Ile172Val Conflicting classifications of pathogenicity ★ ⚠ same residue
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 c.1248+2dup Likely pathogenic ★ same condition
BBS4 p.Ala228fs Pathogenic ★ same condition
BBS4 p.Asp442fs 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-ile172fs (accessed [today's date]).

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