Is BBS2 p.Arg632Cys (c.1894C>T) pathogenic?

BBS2 p.Arg632Cys (c.1894C>T) is classified Conflicting classifications of pathogenicity in BBS2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-08-22). AlphaMissense: ambiguous (0.5244); Ultra-rare (popmax 0.0312%, eas); Associated with Bardet-Biedl syndrome 2.

What condition is associated with BBS2 p.Arg632Cys (c.1894C>T)?

BBS2 p.Arg632Cys (c.1894C>T) is associated with Bardet-Biedl syndrome 2, retinitis pigmentosa 74, Bardet-Biedl syndrome (ClinVar).

How common is BBS2 p.Arg632Cys (c.1894C>T) in the general population?

BBS2 p.Arg632Cys (c.1894C>T) is ultra-rare (popmax 0.0312%, eas) (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.Arg632Cys (c.1894C>T)?

AlphaMissense predicts ambiguous (score 0.5244) — an in-silico prediction, not a clinical call.

BBS2 p.Arg632Cys

c.1894C>T · rs200021475 · VCV319852

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.5244 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Bardet-Biedl syndrome 2

Computational evidence

Protein change
AlphaMissense	0.5244	ambiguous
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -13.16	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, 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 0.0312% East Asian · 14/44,870 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.00205% 33/1,613,402 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0312%	3,205
Admixed American	0.005%	20,002
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)	0.00119%	84,249

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.Arg632Cys
Coding: c.1894C>T
MANE Select: NM_031885
dbSNP: rs200021475
Type: single nucleotide variant
Location: chr16:56496983 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49
Residue 632: a UniProt-annotated variant site (in bbs2 and rp74)

Full BBS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Bardet-Biedl syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 74 Bardet-Biedl syndrome 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 p.Arg632Pro Pathogenic/Likely pathogenic ★★ same residue
BBS2 p.Arg632His Uncertain significance ★★ ⚠ same residue
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

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-arg632cys (accessed [today's date]).

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