Is BBS12 p.Ala615Asp (c.1844C>A) pathogenic?

BBS12 p.Ala615Asp (c.1844C>A) is classified Uncertain significance in BBS12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-15). AlphaMissense: likely pathogenic (0.7673); Very rare (popmax 0.00833%, amr); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS12 p.Ala615Asp (c.1844C>A)?

BBS12 p.Ala615Asp (c.1844C>A) is associated with Bardet-Biedl syndrome (ClinVar).

How common is BBS12 p.Ala615Asp (c.1844C>A) in the general population?

BBS12 p.Ala615Asp (c.1844C>A) is very rare (popmax 0.00833%, 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 BBS12 p.Ala615Asp (c.1844C>A)?

AlphaMissense predicts likely pathogenic (score 0.7673) — an in-silico prediction, not a clinical call.

BBS12 p.Ala615Asp

c.1844C>A · rs17857451 · VCV850852

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7673 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.7673	likely pathogenic · top 7% in BBS12
REVEL	0.606	indeterminate
SaProt	LLR -15.22	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 2,129 bp · p 0.0042 · regional, not allelic
Overall
CADD	24.1	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 0.00833% Admixed American · 5/60,020 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.00031% 5/1,614,174 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.Ala615Asp
Coding: c.1844C>A
MANE Select: NM_152618
dbSNP: rs17857451
Type: single nucleotide variant
Location: chr4:122743736 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.92
Residue 615: a UniProt-annotated variant site (in)

Full BBS12 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

BBS12 p.Ala615= Likely benign ★ same residue
BBS12 p.Ala289Pro Likely pathogenic ★★ same condition
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

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-ala615asp (accessed [today's date]).

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