Is BBS12 p.Ala289Pro (c.865G>C) pathogenic?

BBS12 p.Ala289Pro (c.865G>C) is classified Likely pathogenic in BBS12 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2023-12-28). AlphaMissense: likely pathogenic (0.9225); Very rare (popmax 0.00102%, nfe); Associated with BBS12-related disorder.

What condition is associated with BBS12 p.Ala289Pro (c.865G>C)?

BBS12 p.Ala289Pro (c.865G>C) is associated with BBS12-related disorder, Bardet-Biedl syndrome 12, Bardet-Biedl syndrome (ClinVar).

How common is BBS12 p.Ala289Pro (c.865G>C) in the general population?

BBS12 p.Ala289Pro (c.865G>C) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about BBS12 p.Ala289Pro (c.865G>C)?

AlphaMissense predicts likely pathogenic (score 0.9225) — an in-silico prediction, not a clinical call.

BBS12 p.Ala289Pro

c.865G>C · rs121918328 · VCV1150

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9225 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BBS12-related disorder

Computational evidence

Protein change
AlphaMissense	0.9225	likely pathogenic ✓ concordant with ClinVar · top 2% in BBS12
REVEL	0.657	pathogenic-leaning
SaProt	LLR -13.79	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 2,129 bp · p 0.0042 · regional, not allelic
Overall
CADD	24.2	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 0.00102% European (non-Finnish) · 12/1,180,028 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000821% 12/1,461,878 alleles · very rare

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: BBS12
Protein: p.Ala289Pro
Coding: c.865G>C
MANE Select: NM_152618
dbSNP: rs121918328
Type: single nucleotide variant
Location: chr4:122742757 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.92
Residue 289: a UniProt-annotated variant site (in bbs12; significantly reduces the interaction with mkks; shows significantly decreased interaction with bbs7; the interaction with bbs10 is not affected by this mutation)

Full BBS12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

BBS12-related disorder

Also linked: Bardet-Biedl syndrome 12 Bardet-Biedl syndrome

Similar variants

BBS12 p.Ala289Glu Uncertain significance ⚠ same residue
BBS12 p.Arg214Ter Pathogenic/Likely pathogenic ★★ same condition
BBS12 p.Arg355Ter Pathogenic ★★ same condition
BBS12 p.Arg675Ter Pathogenic/Likely pathogenic ★★ same condition
BBS12 p.Gln149Ter Pathogenic/Likely pathogenic ★★ same condition
BBS12 p.Gln228Ter Pathogenic/Likely pathogenic ★★ same condition
BBS12 p.Gln300Ter Pathogenic ★★ same condition
BBS12 p.Gln402Ter 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/bbs12-p-ala289pro (accessed [today's date]).

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