Is BBS2 p.Arg661Cys (c.1981C>T) pathogenic?

BBS2 p.Arg661Cys (c.1981C>T) is classified Uncertain significance in BBS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-08-08). AlphaMissense: likely benign (0.2677); Very rare (popmax 0.00769%, sas); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS2 p.Arg661Cys (c.1981C>T)?

BBS2 p.Arg661Cys (c.1981C>T) is associated with Bardet-Biedl syndrome (ClinVar).

How common is BBS2 p.Arg661Cys (c.1981C>T) in the general population?

BBS2 p.Arg661Cys (c.1981C>T) is very rare (popmax 0.00769%, sas) (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.Arg661Cys (c.1981C>T)?

AlphaMissense predicts likely benign (score 0.2677) — an in-silico prediction, not a clinical call.

BBS2 p.Arg661Cys

c.1981C>T · rs766476238 · VCV1518264

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2677 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.2677	likely benign
REVEL	0.936	strongly pathogenic-leaning
SaProt	LLR -13.47	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	33.0	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 0.00769% South Asian · 7/91,066 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00124% 20/1,613,612 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,009
Remaining individualsnot grpmax-eligible	0.0032%	31,230
East Asian	0.00223%	44,872
Admixed American	0.00167%	59,996
European (non-Finnish)	0.000763%	131,083

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.Arg661Cys
Coding: c.1981C>T
MANE Select: NM_031885
dbSNP: rs766476238
Type: single nucleotide variant
Location: chr16:56485668 (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 p.Arg661His Uncertain significance ★★ ⚠ same residue
BBS2 p.Arg661Gly Uncertain significance ★ ⚠ same residue
BBS2 p.Arg661Ser Uncertain significance ★ ⚠ 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

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-arg661cys (accessed [today's date]).

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