Is BBS4 p.Ala504= (c.1512G>A) pathogenic?

BBS4 p.Ala504= (c.1512G>A) is classified Conflicting classifications of pathogenicity in BBS4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-09). Ultra-rare (popmax 0.0223%, eas); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS4 p.Ala504= (c.1512G>A)?

BBS4 p.Ala504= (c.1512G>A) is associated with Bardet-Biedl syndrome, Bardet-Biedl syndrome 4 (ClinVar).

How common is BBS4 p.Ala504= (c.1512G>A) in the general population?

BBS4 p.Ala504= (c.1512G>A) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

How is Bardet-Biedl syndrome inherited?

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

BBS4 p.Ala504=

c.1512G>A · rs369958857 · VCV886526

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.7	GERP -3
Overall
CADD	0.935	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0223% East Asian · 10/44,892 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.00161% 26/1,612,720 alleles · ultra-rare exomes 24/1,460,556 · genomes 2/152,164 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,489
South Asian	0.00441%	22,655
Admixed American	0.00167%	59,820
African / African-American	0.00134%	74,878
European (non-Finnish)	0.000848%	117,955

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: BBS4
Protein: p.Ala504=
Coding: c.1512G>A
MANE Select: NM_033028
dbSNP: rs369958857
Type: single nucleotide variant
Location: chr15:72737539 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 504: the 'required for localization to centrosomes' region; the 'disordered' region

Full BBS4 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 4

For Bardet-Biedl syndrome (Orphanet):

Inheritance: Autosomal recessive, Oligogenic
Onset: Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Specific population)

Similar variants

BBS4 p.Ala504Thr Uncertain significance ★ ⚠ same residue
BBS4 p.Ala504Val Conflicting classifications of pathogenicity ★ ⚠ same residue
BBS4 p.Ala504Glu Uncertain significance ★ ⚠ same residue
BBS4 c.1106+2T>A Pathogenic/Likely pathogenic ★★ same condition
BBS4 c.1248+1G>A Pathogenic/Likely pathogenic ★★ same condition
BBS4 c.1248+1G>T Pathogenic ★★ same condition
BBS4 c.1248+2T>C Pathogenic/Likely pathogenic ★★ same condition
BBS4 c.1249-2A>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/bbs4-p-ala504 (accessed [today's date]).

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