Is BBS4 p.Ser464Pro (c.1390T>C) pathogenic?

BBS4 p.Ser464Pro (c.1390T>C) is classified Uncertain significance in BBS4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-15). AlphaMissense: ambiguous (0.3627); Very rare (popmax 0.00223%, eas); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS4 p.Ser464Pro (c.1390T>C)?

BBS4 p.Ser464Pro (c.1390T>C) is associated with Bardet-Biedl syndrome, Bardet-Biedl syndrome 4 (ClinVar).

How common is BBS4 p.Ser464Pro (c.1390T>C) in the general population?

BBS4 p.Ser464Pro (c.1390T>C) is very rare (popmax 0.00223%, 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 BBS4 p.Ser464Pro (c.1390T>C)?

AlphaMissense predicts ambiguous (score 0.3627) — an in-silico prediction, not a clinical call.

BBS4 p.Ser464Pro

c.1390T>C · rs776847398 · VCV1059720

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3627 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.3627	ambiguous
REVEL	0.414	indeterminate
SaProt	LLR -7.09	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	23.8	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 0.00223% East Asian · 1/44,884 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000547% 8/1,461,888 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
South Asian	0.0022%	45,540
European (non-Finnish)	0.000424%	236,006

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.Ser464Pro
Coding: c.1390T>C
MANE Select: NM_033028
dbSNP: rs776847398
Type: single nucleotide variant
Location: chr15:72736903 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 464: 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.Ser464Cys Uncertain significance ★ ⚠ same residue
BBS4 p.Ser464Phe Uncertain significance ★ ⚠ same residue
BBS4 p.Ser464fs Pathogenic/Likely pathogenic ★★ 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-ser464pro (accessed [today's date]).

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