Is BBS12 p.Val8Ile (c.22G>A) pathogenic?

BBS12 p.Val8Ile (c.22G>A) is classified Conflicting classifications of pathogenicity in BBS12 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-19). AlphaMissense: likely benign (0.0622); Very rare (popmax 0.00144%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BBS12 p.Val8Ile (c.22G>A)?

BBS12 p.Val8Ile (c.22G>A) is associated with Inborn genetic diseases, Bardet-Biedl syndrome (ClinVar).

How common is BBS12 p.Val8Ile (c.22G>A) in the general population?

BBS12 p.Val8Ile (c.22G>A) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about BBS12 p.Val8Ile (c.22G>A)?

AlphaMissense predicts likely benign (score 0.0622) — an in-silico prediction, not a clinical call.

BBS12 p.Val8Ile

c.22G>A · rs1351171130 · VCV2176281

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0622 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0622	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -6.73	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 -1	GERP -3.5
Regional constraint	o/e 0.90	unconstrained · MANE · 2,129 bp · p 0.0042 · regional, not allelic
Overall
CADD	4.841	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 0.00144% European (non-Finnish) · 17/1,180,000 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00254% 41/1,613,916 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0642%	1,558
Finnishnot grpmax-eligible	0.00469%	21,336
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)grpmax	0.00144%	69,412
African / African-American	0.00134%	74,902

Ashkenazi Jewish 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.Val8Ile
Coding: c.22G>A
MANE Select: NM_152618
dbSNP: rs1351171130
Type: single nucleotide variant
Location: chr4:122741914 (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

Similar variants

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
BBS12 p.Gln402Ter 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-val8ile (accessed [today's date]).

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