Is BBS4 p.Asp368Gly (c.1103A>G) pathogenic?

BBS4 p.Asp368Gly (c.1103A>G) is classified Conflicting classifications of pathogenicity in BBS4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-02-05). AlphaMissense: ambiguous (0.4783); Very rare (popmax 0.00266%, afr); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS4 p.Asp368Gly (c.1103A>G)?

BBS4 p.Asp368Gly (c.1103A>G) is associated with Bardet-Biedl syndrome, Bardet-Biedl syndrome 4 (ClinVar).

How common is BBS4 p.Asp368Gly (c.1103A>G) in the general population?

BBS4 p.Asp368Gly (c.1103A>G) is very rare (popmax 0.00266%, afr) (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.Asp368Gly (c.1103A>G)?

AlphaMissense predicts ambiguous (score 0.4783) — an in-silico prediction, not a clinical call.

BBS4 p.Asp368Gly

c.1103A>G · rs772548770 · VCV631741

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4783 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.4783	ambiguous
REVEL	0.862	moderately pathogenic-leaning
SaProt	LLR -8.97	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	Δ1.00	donor gain · deltas
Pangolin	Δ0.87	gain · loss 0.78 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	36.0	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 0.00266% African / African-American · 2/75,050 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000372% 6/1,613,036 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00266%	37,525
Admixed American	0.00167%	60,010
European (non-Finnish)	0.000254%	393,052

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.Asp368Gly
Coding: c.1103A>G
MANE Select: NM_033028
dbSNP: rs772548770
Type: single nucleotide variant
Location: chr15:72735179 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 368: the 'required for localization to centrosomes' region; a UniProt-annotated variant site (in bbs4)

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 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
BBS4 c.220+1G>C 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-asp368gly (accessed [today's date]).

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