Is BBS12 p.Leu56Phe (c.166C>T) pathogenic?

BBS12 p.Leu56Phe (c.166C>T) is classified Uncertain significance in BBS12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-18). AlphaMissense: likely benign (0.2453); Very rare (popmax 0.00223%, eas); Associated with Bardet-Biedl syndrome 12.

What condition is associated with BBS12 p.Leu56Phe (c.166C>T)?

BBS12 p.Leu56Phe (c.166C>T) is associated with Bardet-Biedl syndrome 12, Bardet-Biedl syndrome (ClinVar).

How common is BBS12 p.Leu56Phe (c.166C>T) in the general population?

BBS12 p.Leu56Phe (c.166C>T) is very rare (popmax 0.00223%, eas) (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.Leu56Phe (c.166C>T)?

AlphaMissense predicts likely benign (score 0.2453) — an in-silico prediction, not a clinical call.

BBS12 p.Leu56Phe

c.166C>T · rs751515113 · VCV1408984

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2453 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Bardet-Biedl syndrome 12

Computational evidence

Protein change
AlphaMissense	0.2453	likely benign
REVEL	0.544	indeterminate
SaProt	LLR -5.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 2,129 bp · p 0.0042 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00223% East Asian · 1/44,876 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000616% 9/1,461,840 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00469%	21,341
East Asiangrpmax	0.00223%	44,876
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	0.000339%	295,003

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu56Phe
Coding: c.166C>T
MANE Select: NM_152618
dbSNP: rs751515113
Type: single nucleotide variant
Location: chr4:122742058 (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

Bardet-Biedl syndrome 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bardet-Biedl syndrome

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.Leu56Pro Uncertain significance ★ 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-leu56phe (accessed [today's date]).

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