Is BBS2 p.Ser109Leu (c.326C>T) pathogenic?

BBS2 p.Ser109Leu (c.326C>T) is classified Uncertain significance in BBS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-03-08). AlphaMissense: likely benign (0.1106); Ultra-rare (popmax 0.029%, eas); Associated with Inborn genetic diseases.

What condition is associated with BBS2 p.Ser109Leu (c.326C>T)?

BBS2 p.Ser109Leu (c.326C>T) is associated with Inborn genetic diseases, Bardet-Biedl syndrome, inherited retinal dystrophy (ClinVar).

How common is BBS2 p.Ser109Leu (c.326C>T) in the general population?

BBS2 p.Ser109Leu (c.326C>T) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about BBS2 p.Ser109Leu (c.326C>T)?

AlphaMissense predicts likely benign (score 0.1106) — an in-silico prediction, not a clinical call.

BBS2 p.Ser109Leu

c.326C>T · rs181736797 · VCV2068120

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1106 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1106	likely benign
REVEL	0.486	indeterminate
SaProt	LLR -9.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.029% East Asian · 13/44,880 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.0075% 121/1,613,970 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,452
European (non-Finnish)	0.00839%	11,918
Admixed American	0.00833%	12,004
Remaining individualsnot grpmax-eligible	0.0048%	20,835
Finnishnot grpmax-eligible	0.00156%	64,014

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.Ser109Leu
Coding: c.326C>T
MANE Select: NM_031885
dbSNP: rs181736797
Type: single nucleotide variant
Location: chr16:56514472 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bardet-Biedl syndrome inherited retinal dystrophy

Similar variants

BBS2 p.Ser109Ter Pathogenic/Likely pathogenic ★★ same residue
BBS2 p.Ser109= Conflicting classifications of pathogenicity ★ same residue
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

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-ser109leu (accessed [today's date]).

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