Is BBS2 p.Arg661His (c.1982G>A) pathogenic?

BBS2 p.Arg661His (c.1982G>A) is classified Uncertain significance in BBS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-02-25). AlphaMissense: likely benign (0.2828); Ultra-rare (popmax 0.0174%, afr); Associated with Inborn genetic diseases.

What condition is associated with BBS2 p.Arg661His (c.1982G>A)?

BBS2 p.Arg661His (c.1982G>A) is associated with Inborn genetic diseases, Bardet-Biedl syndrome 2, Bardet-Biedl syndrome (ClinVar).

How common is BBS2 p.Arg661His (c.1982G>A) in the general population?

BBS2 p.Arg661His (c.1982G>A) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about BBS2 p.Arg661His (c.1982G>A)?

AlphaMissense predicts likely benign (score 0.2828) — an in-silico prediction, not a clinical call.

BBS2 p.Arg661His

c.1982G>A · rs747686535 · VCV839337

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2828 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2828	likely benign
REVEL	0.943	strongly pathogenic-leaning
SaProt	LLR -12.85	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 2.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	27.1	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 0.0174% African / African-American · 13/74,892 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00787% 127/1,613,848 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,761
European (non-Finnish)	0.00924%	10,825
South Asian	0.00329%	30,361
Remaining individualsnot grpmax-eligible	0.0032%	31,242

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.Arg661His
Coding: c.1982G>A
MANE Select: NM_031885
dbSNP: rs747686535
Type: single nucleotide variant
Location: chr16:56485667 (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 2 Bardet-Biedl syndrome

Similar variants

BBS2 p.Arg661Cys 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.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

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-arg661his (accessed [today's date]).

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