Is BBS12 p.Leu413Val (c.1237C>G) pathogenic?

BBS12 p.Leu413Val (c.1237C>G) is classified Conflicting classifications of pathogenicity in BBS12 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.1742); Very rare (popmax 0.00856%, nfe); Associated with BBS12-related disorder.

What condition is associated with BBS12 p.Leu413Val (c.1237C>G)?

BBS12 p.Leu413Val (c.1237C>G) is associated with BBS12-related disorder, Bardet-Biedl syndrome 12, Bardet-Biedl syndrome (ClinVar).

How common is BBS12 p.Leu413Val (c.1237C>G) in the general population?

BBS12 p.Leu413Val (c.1237C>G) is very rare (popmax 0.00856%, nfe) (gnomAD).

What do computational predictors say about BBS12 p.Leu413Val (c.1237C>G)?

AlphaMissense predicts likely benign (score 0.1742) — an in-silico prediction, not a clinical call.

BBS12 p.Leu413Val

c.1237C>G · rs758217005 · VCV444641

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00856%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

BBS12-related disorder

Computational evidence

Protein change
AlphaMissense	0.1742	likely benign
REVEL	0.447	indeterminate
SaProt	LLR -10.16	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.56	GERP 0.067, phastCons 0.075
Regional constraint	o/e 0.90	unconstrained · MANE · 2,129 bp · p 0.0042 · regional, not allelic
Overall
CADD	20.7	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 0.00856% European (non-Finnish) · 101/1,180,056 alleles

Filtering AF 0.00716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00668%

Overall 0.00644% 104/1,614,102 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00856%	11,684
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00133%	74,922

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.Leu413Val
Coding: c.1237C>G
MANE Select: NM_152618
dbSNP: rs758217005
Type: single nucleotide variant
Location: chr4:122743129 (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

BBS12-related disorder

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

Similar variants

BBS12 p.Leu413= 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-leu413val (accessed [today's date]).

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