Is BBS12 p.Arg487Lys (c.1460G>A) pathogenic?

BBS12 p.Arg487Lys (c.1460G>A) is classified Conflicting classifications of pathogenicity in BBS12 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-06-12). AlphaMissense: likely benign (0.0861); Ultra-rare (popmax 0.0283%, amr); Associated with Inborn genetic diseases.

What condition is associated with BBS12 p.Arg487Lys (c.1460G>A)?

BBS12 p.Arg487Lys (c.1460G>A) is associated with Inborn genetic diseases, Bardet-Biedl syndrome 12, Bardet-Biedl syndrome (ClinVar).

How common is BBS12 p.Arg487Lys (c.1460G>A) in the general population?

BBS12 p.Arg487Lys (c.1460G>A) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about BBS12 p.Arg487Lys (c.1460G>A)?

AlphaMissense predicts likely benign (score 0.0861) — an in-silico prediction, not a clinical call.

BBS12 p.Arg487Lys

c.1460G>A · rs376531209 · VCV851247

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0861 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0861	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -5.14	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 2.5	GERP -1.1, phastCons 0.078
Regional constraint	o/e 0.90	unconstrained · MANE · 2,129 bp · p 0.0042 · regional, not allelic
Overall
CADD	4.345	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 0.0283% Admixed American · 17/60,028 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00211% 34/1,614,192 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0283%	3,531
African / African-American	0.0213%	4,690
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Arg487Lys
Coding: c.1460G>A
MANE Select: NM_152618
dbSNP: rs376531209
Type: single nucleotide variant
Location: chr4:122743352 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.92

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

BBS12 p.Arg487Gly Uncertain significance ★★ ⚠ same residue
BBS12 p.Arg487= 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

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-arg487lys (accessed [today's date]).

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