Is BBS2 p.Arg403His (c.1208G>A) pathogenic?

BBS2 p.Arg403His (c.1208G>A) is classified Uncertain significance in BBS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-02). AlphaMissense: likely benign (0.0594); Very rare (popmax 0.00458%, nfe); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS2 p.Arg403His (c.1208G>A)?

BBS2 p.Arg403His (c.1208G>A) is associated with Bardet-Biedl syndrome, Bardet-Biedl syndrome 2, retinitis pigmentosa 74 (ClinVar).

How common is BBS2 p.Arg403His (c.1208G>A) in the general population?

BBS2 p.Arg403His (c.1208G>A) is very rare (popmax 0.00458%, nfe) (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.Arg403His (c.1208G>A)?

AlphaMissense predicts likely benign (score 0.0594) — an in-silico prediction, not a clinical call.

BBS2 p.Arg403His

c.1208G>A · rs192007013 · VCV2189701

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0594 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00458%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.0594	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.21	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 2.7	GERP 1.4, phastCons 0.96
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	17.76	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 0.00458% European (non-Finnish) · 54/1,180,002 alleles

Filtering AF 0.00358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00353% 57/1,613,824 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00458%	21,852
South Asian	0.0022%	45,534
African / African-American	0.00134%	74,894

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.Arg403His
Coding: c.1208G>A
MANE Select: NM_031885
dbSNP: rs192007013
Type: single nucleotide variant
Location: chr16:56501370 (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

Also linked: Bardet-Biedl syndrome 2 retinitis pigmentosa 74

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.Arg403Leu Uncertain significance ★★ ⚠ same residue
BBS2 p.Arg403= Likely benign ★★ same residue
BBS2 p.Arg403Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
BBS2 p.Arg403Pro Uncertain significance ★ ⚠ same residue
BBS2 p.Arg403fs Pathogenic/Likely pathogenic ★★ 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

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-arg403his (accessed [today's date]).

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