Is BBS2 p.Val596Met (c.1786G>A) pathogenic?

BBS2 p.Val596Met (c.1786G>A) is classified Uncertain significance in BBS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-06-06). AlphaMissense: likely benign (0.1439); Ultra-rare (popmax 0.0174%, afr); Associated with Bardet-Biedl syndrome 2.

What condition is associated with BBS2 p.Val596Met (c.1786G>A)?

BBS2 p.Val596Met (c.1786G>A) is associated with Bardet-Biedl syndrome 2, retinitis pigmentosa 74, Bardet-Biedl syndrome (ClinVar).

How common is BBS2 p.Val596Met (c.1786G>A) in the general population?

BBS2 p.Val596Met (c.1786G>A) is ultra-rare (popmax 0.0174%, afr) (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 BBS2 p.Val596Met (c.1786G>A)?

AlphaMissense predicts likely benign (score 0.1439) — an in-silico prediction, not a clinical call.

BBS2 p.Val596Met

c.1786G>A · rs375828912 · VCV1412652

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1439 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Bardet-Biedl syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1439	likely benign
REVEL	0.48	indeterminate
SaProt	LLR -9.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.38	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 3.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	22.8	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 0.0174% African / African-American · 13/74,870 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00093% 15/1,613,340 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,759
Admixed American	0.00167%	59,976
European (non-Finnish)	8.48e-05%	1,179,857

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: BBS2
Protein: p.Val596Met
Coding: c.1786G>A
MANE Select: NM_031885
dbSNP: rs375828912
Type: single nucleotide variant
Location: chr16:56497754 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49

Full BBS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Bardet-Biedl syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 74 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

BBS2 p.Val596Leu Uncertain significance ★ ⚠ same residue
BBS2 c.118-1G>T Likely pathogenic ★★ same condition
BBS2 c.118-2A>C Likely pathogenic ★★ same condition
BBS2 c.118-2A>G Likely pathogenic ★★ same condition
BBS2 c.1225+2T>C Likely pathogenic ★★ same condition
BBS2 c.1225+2T>G Likely pathogenic ★★ same condition
BBS2 c.1397+1G>A Pathogenic/Likely pathogenic ★★ same condition
BBS2 c.1397+2T>C 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/bbs2-p-val596met (accessed [today's date]).

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