Is BBS2 p.Leu221fs (c.661del) pathogenic?

BBS2 p.Leu221fs (c.661del) is classified Pathogenic in BBS2 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-09-22). Very rare (popmax 0.000932%, nfe); Associated with retinitis pigmentosa 74.

What condition is associated with BBS2 p.Leu221fs (c.661del)?

BBS2 p.Leu221fs (c.661del) is associated with retinitis pigmentosa 74, Bardet-Biedl syndrome 2, Bardet-Biedl syndrome (ClinVar).

How common is BBS2 p.Leu221fs (c.661del) in the general population?

BBS2 p.Leu221fs (c.661del) is very rare (popmax 0.000932%, nfe) (gnomAD).

How is Retinitis pigmentosa inherited?

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

BBS2 p.Leu221fs

c.661del · rs770258677 · VCV208564

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Conditions

retinitis pigmentosa 74

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 6 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.4	GERP 1.9, phastCons 1
Overall
CADD	34.0	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 0.000932% European (non-Finnish) · 11/1,179,978 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.0013% 21/1,613,972 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0156%	6,399
European (non-Finnish)grpmax	0.000932%	107,271

Finnish 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: BBS2
Protein: p.Leu221fs
Coding: c.661del
MANE Select: NM_031885
dbSNP: rs770258677
Type: Deletion
Location: chr16:56506176 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49

Full BBS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinitis pigmentosa 74 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bardet-Biedl syndrome 2 Bardet-Biedl syndrome retinitis pigmentosa

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

BBS2 p.Leu221Pro Uncertain significance ★★ ⚠ same residue
BBS2 p.Leu221Phe Uncertain significance ★ ⚠ same residue
BBS2 c.472del Pathogenic/Likely pathogenic ★★ same condition
BBS2 c.804+1_804+14del Likely pathogenic ★★ same condition
BBS2 c.940+1del Pathogenic/Likely pathogenic ★★ same condition
BBS2 p.Arg339fs Pathogenic/Likely pathogenic ★★ same condition
BBS2 p.Asn258fs Pathogenic/Likely pathogenic ★★ same condition
BBS2 p.Asp371fs 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/bbs2-p-leu221fs (accessed [today's date]).

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