Is BBS2 p.Thr331Ala (c.991A>G) pathogenic?

BBS2 p.Thr331Ala (c.991A>G) is classified Uncertain significance in BBS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.0606); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with BBS2 p.Thr331Ala (c.991A>G)?

BBS2 p.Thr331Ala (c.991A>G) is associated with Inborn genetic diseases (ClinVar).

How common is BBS2 p.Thr331Ala (c.991A>G) in the general population?

BBS2 p.Thr331Ala (c.991A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BBS2 p.Thr331Ala (c.991A>G)?

AlphaMissense predicts likely benign (score 0.0606) — an in-silico prediction, not a clinical call.

BBS2 p.Thr331Ala

c.991A>G · VCV4198753

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0606 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0606	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR -6.51	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 0.3	GERP -1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	14.98	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BBS2
Protein: p.Thr331Ala
Coding: c.991A>G
MANE Select: NM_031885
Type: single nucleotide variant
Location: chr16:56502406 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BBS2 p.Thr331Asn Uncertain significance ★ ⚠ same residue
BBS2 p.Thr331Ile Uncertain significance ★ ⚠ same residue
BBS2 p.Thr331Ser Uncertain significance ★ ⚠ same residue
BBS2 p.Thr331= Likely benign ★ same residue
BBS2 p.Ala682Thr Uncertain significance ★★ ⚠ same condition
BBS2 p.Arg353Cys Uncertain significance ★★ ⚠ same condition
BBS2 p.Arg374Gln Uncertain significance ★★ ⚠ same condition
BBS2 p.Arg539Gln Uncertain significance ★★ ⚠ 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-thr331ala (accessed [today's date]).

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