Is BBS2 p.Ala136fs (c.406dup) pathogenic?

BBS2 p.Ala136fs (c.406dup) is classified Likely pathogenic in BBS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-23). Very rare (popmax 0.0022%, sas); Associated with Bardet-Biedl syndrome 2.

What condition is associated with BBS2 p.Ala136fs (c.406dup)?

BBS2 p.Ala136fs (c.406dup) is associated with Bardet-Biedl syndrome 2, retinitis pigmentosa 74 (ClinVar).

How common is BBS2 p.Ala136fs (c.406dup) in the general population?

BBS2 p.Ala136fs (c.406dup) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Bardet-Biedl syndrome inherited?

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

BBS2 p.Ala136fs

c.406dup · rs756003832 · VCV2680016

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

Bardet-Biedl syndrome 2

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 3 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.7	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 0.0022% South Asian · 2/91,078 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000248% 4/1,613,850 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,539
African / African-American	0.00134%	74,906
European (non-Finnish)	8.48e-05%	1,179,928

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.Ala136fs
Coding: c.406dup
MANE Select: NM_031885
dbSNP: rs756003832
Type: Duplication
Location: chr16:56511223 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49
Residue 136: a UniProt-annotated variant site (in bbs2)

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

Disease context

Bardet-Biedl syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 74

For Bardet-Biedl syndrome (Orphanet):

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

Similar variants

BBS2 p.Ala136= Conflicting classifications of pathogenicity ★ same residue
BBS2 p.Ala136Val Uncertain significance ★ ⚠ same residue
BBS2 p.Ala615fs Pathogenic/Likely pathogenic ★★ same condition
BBS2 p.Arg403fs Pathogenic/Likely pathogenic ★★ same condition
BBS2 p.Asn663Ter Pathogenic/Likely pathogenic ★★ same condition
BBS2 p.Leu367fs Pathogenic/Likely pathogenic ★★ same condition
BBS2 p.Leu62fs Likely pathogenic ★★ same condition
BBS2 p.Thr555fs 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/bbs2-p-ala136fs (accessed [today's date]).

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