Is BBS4 p.Ala391Val (c.1172C>T) pathogenic?

BBS4 p.Ala391Val (c.1172C>T) is classified Uncertain significance in BBS4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-05-21). AlphaMissense: likely pathogenic (0.737); Ultra-rare (popmax 0.01%, amr); Associated with Bardet-Biedl syndrome 4.

What condition is associated with BBS4 p.Ala391Val (c.1172C>T)?

BBS4 p.Ala391Val (c.1172C>T) is associated with Bardet-Biedl syndrome 4, Bardet-Biedl syndrome (ClinVar).

How common is BBS4 p.Ala391Val (c.1172C>T) in the general population?

BBS4 p.Ala391Val (c.1172C>T) is ultra-rare (popmax 0.01%, amr) (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.Ala391Val (c.1172C>T)?

AlphaMissense predicts likely pathogenic (score 0.737) — an in-silico prediction, not a clinical call.

BBS4 p.Ala391Val

c.1172C>T · rs1419955498 · VCV434495

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.737 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bardet-Biedl syndrome 4

Computational evidence

Protein change
AlphaMissense	0.737	likely pathogenic
REVEL	0.757	pathogenic-leaning
SaProt	LLR -15.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	25.6	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 0.01% Admixed American · 6/60,000 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00062% 10/1,613,976 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,000
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.000169%	589,995

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.Ala391Val
Coding: c.1172C>T
MANE Select: NM_033028
dbSNP: rs1419955498
Type: single nucleotide variant
Location: chr15:72735890 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 391: the 'required for localization to centrosomes' region

Full BBS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Bardet-Biedl syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bardet-Biedl syndrome

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.Ala391Thr Uncertain significance ★★ ⚠ same residue
BBS4 p.Ala391= 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

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-ala391val (accessed [today's date]).

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