Is BBS2 p.Lys449Arg (c.1346A>G) pathogenic?

BBS2 p.Lys449Arg (c.1346A>G) is classified Uncertain significance in BBS2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-15). AlphaMissense: likely benign (0.0759); Very rare (popmax 0.004%, afr).

How common is BBS2 p.Lys449Arg (c.1346A>G) in the general population?

BBS2 p.Lys449Arg (c.1346A>G) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about BBS2 p.Lys449Arg (c.1346A>G)?

AlphaMissense predicts likely benign (score 0.0759) — an in-silico prediction, not a clinical call.

BBS2 p.Lys449Arg

c.1346A>G · VCV3357579

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0759 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0759	likely benign
REVEL	0.699	pathogenic-leaning
SaProt	LLR -7.02	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.5, 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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,920 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,614,052 alleles · very rare

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.Lys449Arg
Coding: c.1346A>G
MANE Select: NM_031885
Type: single nucleotide variant
Location: chr16:56500905 (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

Similar variants

BBS2 p.Lys449Glu Uncertain significance ★ ⚠ same residue
OGFOD1 p.Leu449Phe Uncertain significance ★ ⚠ same residue
BBS2 p.Lys449fs Pathogenic ★ same residue
BBS2 c.118-1G>T Likely pathogenic ★★ same type
BBS2 c.118-2A>C Likely pathogenic ★★ same type
BBS2 c.118-2A>G Likely pathogenic ★★ same type
BBS2 c.1225+2T>C Likely pathogenic ★★ same type
BBS2 c.1225+2T>G Likely pathogenic ★★ same type

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-lys449arg (accessed [today's date]).

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