Is BBS2 p.Ile42Met (c.126T>G) pathogenic?

BBS2 p.Ile42Met (c.126T>G) is classified Conflicting classifications of pathogenicity in BBS2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.2648); Ultra-rare (popmax 0.0199%, nfe); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS2 p.Ile42Met (c.126T>G)?

BBS2 p.Ile42Met (c.126T>G) is associated with Bardet-Biedl syndrome, Bardet-Biedl syndrome 2 (ClinVar).

How common is BBS2 p.Ile42Met (c.126T>G) in the general population?

BBS2 p.Ile42Met (c.126T>G) is ultra-rare (popmax 0.0199%, nfe) (gnomAD).

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.Ile42Met (c.126T>G)?

AlphaMissense predicts likely benign (score 0.2648) — an in-silico prediction, not a clinical call.

BBS2 p.Ile42Met

c.126T>G · rs139945733 · VCV699798

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2648 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0199%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.2648	likely benign
REVEL	0.669	pathogenic-leaning
SaProt	LLR -9.25	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 0.53, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	24.5	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 0.0199% European (non-Finnish) · 235/1,178,646 alleles

Filtering AF 0.0178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.017%

Overall 0.038% 612/1,612,452 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.542%	185
Remaining individualsnot grpmax-eligible	0.0336%	2,975
European (non-Finnish)grpmax	0.0199%	5,016
South Asian	0.0099%	10,097

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.Ile42Met
Coding: c.126T>G
MANE Select: NM_031885
dbSNP: rs139945733
Type: single nucleotide variant
Location: chr16:56514672 (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

Also linked: Bardet-Biedl syndrome 2

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-ile42met (accessed [today's date]).

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