Is BBS2 p.Ile123Val (c.367A>G) pathogenic?

BBS2 p.Ile123Val (c.367A>G) is classified Conflicting classifications of pathogenicity in BBS2 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0561); Common (popmax 41%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Bardet-Biedl syndrome.

What condition is associated with BBS2 p.Ile123Val (c.367A>G)?

BBS2 p.Ile123Val (c.367A>G) is associated with Bardet-Biedl syndrome, Bardet-Biedl syndrome 1, Bardet-Biedl syndrome 2 (ClinVar).

How is Bardet-Biedl syndrome inherited?

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

What do computational predictors say about BBS2 p.Ile123Val (c.367A>G)?

AlphaMissense predicts likely benign (score 0.0561) — an in-silico prediction, not a clinical call.

BBS2 p.Ile123Val

Q: How common is BBS2 p.Ile123Val (c.367A>G) in the general population?

BBS2 p.Ile123Val (c.367A>G) is common (popmax 41%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.367A>G · rs11373 · VCV261981

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.0561 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 41%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.0561	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -5.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.82	GERP -1.3, phastCons 0.001
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	9.008	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 41% East Asian · 18,373/44,852 alleles

Filtering AF 40.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 40.3%

Overall 18.9% 304,683/1,613,704 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	41%	2
Admixed American	27.5%	4
African / African-American	23.1%	4
Ashkenazi Jewishnot grpmax-eligible	21.1%	5
Remaining individualsnot grpmax-eligible	19.9%	5
South Asian	18.8%	5
Finnishnot grpmax-eligible	17.5%	6
European (non-Finnish)	17.3%	6
Middle Eastern	15%	7
Amishnot grpmax-eligible	10.2%	10

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.Ile123Val
Coding: c.367A>G
MANE Select: NM_031885
dbSNP: rs11373
Type: single nucleotide variant
Location: chr16:56511263 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49
Residue 123: a UniProt-annotated variant site (in)

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

Also linked: Bardet-Biedl syndrome 1 Bardet-Biedl syndrome 2 retinitis pigmentosa 74 inherited retinal dystrophy

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.118-2A>G Likely pathogenic ★★ same condition
BBS2 c.1225+2T>C Likely pathogenic ★★ same condition
BBS2 c.1225+2T>G 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

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-ile123val (accessed [today's date]).

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