Is BBS4 p.Ala288Val (c.863C>T) pathogenic?

BBS4 p.Ala288Val (c.863C>T) is classified Uncertain significance in BBS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-15). AlphaMissense: likely pathogenic (0.7476); Very rare (popmax 0.00446%, eas); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS4 p.Ala288Val (c.863C>T)?

BBS4 p.Ala288Val (c.863C>T) is associated with Bardet-Biedl syndrome (ClinVar).

How common is BBS4 p.Ala288Val (c.863C>T) in the general population?

BBS4 p.Ala288Val (c.863C>T) is very rare (popmax 0.00446%, 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.Ala288Val (c.863C>T)?

AlphaMissense predicts likely pathogenic (score 0.7476) — an in-silico prediction, not a clinical call.

BBS4 p.Ala288Val

c.863C>T · rs772051835 · VCV1503607

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7476 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.7476	likely pathogenic
REVEL	0.433	indeterminate
SaProt	LLR -12.81	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00446% East Asian · 2/44,876 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00192% 31/1,614,014 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,438
European (non-Finnish)	0.00229%	43,706
South Asian	0.0022%	45,541

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.Ala288Val
Coding: c.863C>T
MANE Select: NM_033028
dbSNP: rs772051835
Type: single nucleotide variant
Location: chr15:72731456 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 288: the 'interaction with pcm1' 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

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.Ala288= Conflicting classifications of pathogenicity ★ same residue
BBS4 p.Ala288Glu 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
BBS4 c.157-2A>G 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-ala288val (accessed [today's date]).

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