Is BBS4 p.Ala2Val (c.5C>T) pathogenic?

BBS4 p.Ala2Val (c.5C>T) is classified Uncertain significance in BBS4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-17). AlphaMissense: ambiguous (0.4945); Very rare (popmax 0.00237%, eas); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS4 p.Ala2Val (c.5C>T)?

BBS4 p.Ala2Val (c.5C>T) is associated with Bardet-Biedl syndrome (ClinVar).

How common is BBS4 p.Ala2Val (c.5C>T) in the general population?

BBS4 p.Ala2Val (c.5C>T) is very rare (popmax 0.00237%, 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.Ala2Val (c.5C>T)?

AlphaMissense predicts ambiguous (score 0.4945) — an in-silico prediction, not a clinical call.

BBS4 p.Ala2Val

c.5C>T · rs923399180 · VCV1375048

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4945 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, eas)

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.4945	ambiguous
REVEL	0.418	indeterminate
SaProt	LLR -8.43	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.58 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5	GERP 3.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	24.3	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 0.00237% East Asian · 1/42,280 alleles

Overall 0.000128% 2/1,565,338 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00237%	42,280
European (non-Finnish)	8.65e-05%	1,155,920

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.Ala2Val
Coding: c.5C>T
MANE Select: NM_033028
dbSNP: rs923399180
Type: single nucleotide variant
Location: chr15:72686232 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 2: 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

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.Ala2= Likely benign ★★ 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
BBS4 c.157-3C>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-ala2val (accessed [today's date]).

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