Is BBS2 p.Ala136Glu (c.407C>A) pathogenic?

BBS2 p.Ala136Glu (c.407C>A) is classified Uncertain significance in BBS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-19). AlphaMissense: likely pathogenic (0.9669); Ultra-rare (popmax 0.0111%, eas); Associated with inherited retinal dystrophy.

What condition is associated with BBS2 p.Ala136Glu (c.407C>A)?

BBS2 p.Ala136Glu (c.407C>A) is associated with inherited retinal dystrophy, Bardet-Biedl syndrome (ClinVar).

How common is BBS2 p.Ala136Glu (c.407C>A) in the general population?

BBS2 p.Ala136Glu (c.407C>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about BBS2 p.Ala136Glu (c.407C>A)?

AlphaMissense predicts likely pathogenic (score 0.9669) — an in-silico prediction, not a clinical call.

BBS2 p.Ala136Glu

c.407C>A · rs373166163 · VCV1907866

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9669 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.9669	likely pathogenic · top 7% in BBS2
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -11.81	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 8.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	26.8	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

Grpmax group 0.0111% East Asian · 5/44,864 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000547% 8/1,461,750 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,973
Remaining individualsnot grpmax-eligible	0.0016%	62,496
European (non-Finnish)	0.00017%	589,960

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.Ala136Glu
Coding: c.407C>A
MANE Select: NM_031885
dbSNP: rs373166163
Type: single nucleotide variant
Location: chr16:56511223 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49
Residue 136: a UniProt-annotated variant site (in bbs2)

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bardet-Biedl syndrome

Similar variants

BBS2 p.Ala136Gly Uncertain significance ★★ ⚠ same residue
BBS2 p.Ala136= Conflicting classifications of pathogenicity ★ same residue
BBS2 p.Ala136Val Uncertain significance ★ ⚠ same residue
BBS2 c.118-1G>T Likely pathogenic ★★ same condition
BBS2 c.118-2A>C Likely pathogenic ★★ same condition
BBS2 c.1225+2T>C 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-ala136glu (accessed [today's date]).

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