Is BBS9 p.Ser252Phe (c.755C>T) pathogenic?

BBS9 p.Ser252Phe (c.755C>T) is classified Uncertain significance in BBS9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-13). AlphaMissense: likely benign (0.1665); Very rare (popmax 0.0022%, sas); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS9 p.Ser252Phe (c.755C>T)?

BBS9 p.Ser252Phe (c.755C>T) is associated with Bardet-Biedl syndrome (ClinVar).

How common is BBS9 p.Ser252Phe (c.755C>T) in the general population?

BBS9 p.Ser252Phe (c.755C>T) is very rare (popmax 0.0022%, sas) (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 BBS9 p.Ser252Phe (c.755C>T)?

AlphaMissense predicts likely benign (score 0.1665) — an in-silico prediction, not a clinical call.

BBS9 p.Ser252Phe

c.755C>T · rs1382587192 · VCV1721521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1665 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.1665	likely benign
REVEL	0.497	indeterminate
SaProt	LLR -11.85	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 459 kb · p 0.062 · regional, not allelic
Overall
CADD	29.4	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 0.0022% South Asian · 2/91,022 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000248% 4/1,613,420 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,511
European (non-Finnish)	0.00017%	589,856

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: BBS9
Protein: p.Ser252Phe
Coding: c.755C>T
MANE Select: NM_198428
dbSNP: rs1382587192
Type: single nucleotide variant
Location: chr7:33273064 (GRCh38)
Gene constraint: LOEUF 0.959 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.41 · 2 PDB
Residue 252: the 'seven-bladed beta-propeller' region

Full BBS9 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

BBS9 p.Ser252fs Pathogenic ★ same residue
BBS9 c.1329+1738C>T Likely pathogenic ★★ same condition
BBS9 c.1552+2T>A Likely pathogenic ★★ same condition
BBS9 c.1693+1G>A Pathogenic/Likely pathogenic ★★ same condition
BBS9 c.1789+1G>A Pathogenic/Likely pathogenic ★★ same condition
BBS9 c.1789+1G>C Pathogenic/Likely pathogenic ★★ same condition
BBS9 c.2299-2A>C Likely pathogenic ★★ same condition
BBS9 c.2521+1G>T Likely 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/bbs9-p-ser252phe (accessed [today's date]).

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