Is BBS12 p.Leu588Pro (c.1763T>C) pathogenic?

BBS12 p.Leu588Pro (c.1763T>C) is classified Uncertain significance in BBS12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-12). AlphaMissense: likely pathogenic (0.9414); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with BBS12 p.Leu588Pro (c.1763T>C)?

BBS12 p.Leu588Pro (c.1763T>C) is associated with Inborn genetic diseases (ClinVar).

How common is BBS12 p.Leu588Pro (c.1763T>C) in the general population?

BBS12 p.Leu588Pro (c.1763T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BBS12 p.Leu588Pro (c.1763T>C)?

AlphaMissense predicts likely pathogenic (score 0.9414) — an in-silico prediction, not a clinical call.

BBS12 p.Leu588Pro

c.1763T>C · VCV3479917

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9414 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9414	likely pathogenic · top 1% in BBS12
REVEL	0.732	pathogenic-leaning
SaProt	LLR -15.53	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 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 2,129 bp · p 0.0042 · regional, not allelic
Overall
CADD	25.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BBS12
Protein: p.Leu588Pro
Coding: c.1763T>C
MANE Select: NM_152618
Type: single nucleotide variant
Location: chr4:122743655 (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

Similar variants

BBS12 p.Leu588Arg Uncertain significance ★ ⚠ same residue
BBS12 p.Leu588= Likely benign ★ same residue
BBS12 p.Ala23Thr Uncertain significance ★★ ⚠ same condition
BBS12 p.Ala448Val Uncertain significance ★★ ⚠ same condition
BBS12 p.Ala510Thr Uncertain significance ★★ ⚠ same condition
BBS12 p.Arg239Lys Uncertain significance ★★ ⚠ same condition
BBS12 p.Arg421Ser Uncertain significance ★★ ⚠ same condition
BBS12 p.Arg487Gly Uncertain significance ★★ ⚠ 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-leu588pro (accessed [today's date]).

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