Is BBS2 p.Ile561Thr (c.1682T>C) pathogenic?

BBS2 p.Ile561Thr (c.1682T>C) is classified Uncertain significance in BBS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-24). AlphaMissense: likely benign (0.1645); Ultra-rare (popmax 0.0494%, mid); Associated with Inborn genetic diseases.

What condition is associated with BBS2 p.Ile561Thr (c.1682T>C)?

BBS2 p.Ile561Thr (c.1682T>C) is associated with Inborn genetic diseases, Bardet-Biedl syndrome (ClinVar).

How common is BBS2 p.Ile561Thr (c.1682T>C) in the general population?

BBS2 p.Ile561Thr (c.1682T>C) is ultra-rare (popmax 0.0494%, mid) (gnomAD).

What do computational predictors say about BBS2 p.Ile561Thr (c.1682T>C)?

AlphaMissense predicts likely benign (score 0.1645) — an in-silico prediction, not a clinical call.

BBS2 p.Ile561Thr

c.1682T>C · rs745378319 · VCV2153143

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1645 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1645	likely benign
REVEL	0.726	pathogenic-leaning
SaProt	LLR -8.77	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 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	24.0	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 0.0494% Middle Eastern · 3/6,076 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00205% 33/1,611,678 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,025
African / African-American	0.00267%	37,435
European (non-Finnish)	0.00212%	47,195
Admixed American	0.00167%	59,982
Remaining individualsnot grpmax-eligible	0.0016%	62,464
South Asian	0.0011%	91,078

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.Ile561Thr
Coding: c.1682T>C
MANE Select: NM_031885
dbSNP: rs745378319
Type: single nucleotide variant
Location: chr16:56497858 (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

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-p-ile561thr (accessed [today's date]).

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