Is BBS2 c.345+4A>C pathogenic?

BBS2 c.345+4A>C is classified Uncertain significance in BBS2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-05-19). Very rare (popmax 0.00017%, nfe); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS2 c.345+4A>C?

BBS2 c.345+4A>C is associated with Bardet-Biedl syndrome (ClinVar).

How common is BBS2 c.345+4A>C in the general population?

BBS2 c.345+4A>C is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Bardet-Biedl syndrome inherited?

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

BBS2 c.345+4A>C

rs749718244 · VCV1982879

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +4	donor splice region (+4, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.92 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5	GERP 1.7, phastCons 1
Non-coding constraint	Z 1.82	1 kb window · o/e 0.86 · regional · uncalibrated
Overall
CADD	18.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,178,470 alleles

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

Overall 0.000124% 2/1,612,324 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: BBS2
Coding: c.345+4A>C
MANE Select: NM_031885
dbSNP: rs749718244
Type: single nucleotide variant
Location: chr16:56514449 (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

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

BBS2 c.118-1G>T Likely pathogenic ★★ same condition
BBS2 c.118-2A>C Likely pathogenic ★★ same condition
BBS2 c.1225+2T>C Likely pathogenic ★★ same condition
BBS2 c.1397+1G>A Pathogenic/Likely pathogenic ★★ same condition
BBS2 c.1397+2T>C Likely pathogenic ★★ same condition
BBS2 c.1398-2A>G Likely pathogenic ★★ same condition
BBS2 c.1527+1G>A Likely pathogenic ★★ same condition
BBS2 c.345+1G>A 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-c-345-plus-4a-c (accessed [today's date]).

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