Is BBS2 p.Arg506Trp (c.1516C>T) pathogenic?

BBS2 p.Arg506Trp (c.1516C>T) is classified Uncertain significance in BBS2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.2644); Ultra-rare (popmax 0.0306%, afr); Associated with retinitis pigmentosa 74.

What condition is associated with BBS2 p.Arg506Trp (c.1516C>T)?

BBS2 p.Arg506Trp (c.1516C>T) is associated with retinitis pigmentosa 74, Bardet-Biedl syndrome 2, Bardet-Biedl syndrome (ClinVar).

How common is BBS2 p.Arg506Trp (c.1516C>T) in the general population?

BBS2 p.Arg506Trp (c.1516C>T) is ultra-rare (popmax 0.0306%, afr) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BBS2 p.Arg506Trp (c.1516C>T)?

AlphaMissense predicts likely benign (score 0.2644) — an in-silico prediction, not a clinical call.

BBS2 p.Arg506Trp

c.1516C>T · rs560253338 · VCV948185

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2644 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0306%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa 74

Computational evidence

Protein change
AlphaMissense	0.2644	likely benign
REVEL	0.866	moderately pathogenic-leaning
SaProt	LLR -14.28	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 3.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	25.9	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 0.0306% African / African-American · 23/75,044 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0177%

Overall 0.00223% 36/1,614,086 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0306%	3,263
South Asian	0.00769%	13,011
Remaining individualsnot grpmax-eligible	0.0048%	20,833
East Asian	0.00223%	44,874
European (non-Finnish)	0.000169%	589,991

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.Arg506Trp
Coding: c.1516C>T
MANE Select: NM_031885
dbSNP: rs560253338
Type: single nucleotide variant
Location: chr16:56499789 (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

retinitis pigmentosa 74 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bardet-Biedl syndrome 2 Bardet-Biedl syndrome

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

BBS2 p.Arg506Gln Uncertain significance ★ ⚠ same residue
OGFOD1 p.Asp506Asn 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-arg506trp (accessed [today's date]).

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