Is BBS4 p.Lys46Arg (c.137A>G) pathogenic?

BBS4 p.Lys46Arg (c.137A>G) is classified Conflicting classifications of pathogenicity in BBS4 (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.1009); Low-frequency (popmax 1.07%, nfe); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS4 p.Lys46Arg (c.137A>G)?

BBS4 p.Lys46Arg (c.137A>G) is associated with Bardet-Biedl syndrome, Bardet-Biedl syndrome 1, Bardet-Biedl syndrome 4 (ClinVar).

How common is BBS4 p.Lys46Arg (c.137A>G) in the general population?

BBS4 p.Lys46Arg (c.137A>G) is low-frequency (popmax 1.07%, nfe) (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.Lys46Arg (c.137A>G)?

AlphaMissense predicts likely benign (score 0.1009) — an in-silico prediction, not a clinical call.

BBS4 p.Lys46Arg

c.137A>G · rs75295839 · VCV196570

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.1009 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.07%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.1009	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -8.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	22.0	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 1.07% European (non-Finnish) · 12,585/1,179,514 alleles

Filtering AF 1.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.04%

Overall 0.891% 14,375/1,613,402 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.07%	94
Ashkenazi Jewishnot grpmax-eligible	0.993%	101
Remaining individualsnot grpmax-eligible	0.874%	114
Admixed American	0.731%	137
Finnishnot grpmax-eligible	0.349%	286
Middle Eastern	0.215%	466
African / African-American	0.203%	493
South Asian	0.134%	747
East Asian	0.00223%	44,866

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.Lys46Arg
Coding: c.137A>G
MANE Select: NM_033028
dbSNP: rs75295839
Type: single nucleotide variant
Location: chr15:72709760 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 46: the 'required for localization to centrosomes' region; a UniProt-annotated variant site (in)

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 1 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.Lys46= 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-lys46arg (accessed [today's date]).

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