Is BBS2 p.Asn141Ile (c.422A>T) pathogenic?

BBS2 p.Asn141Ile (c.422A>T) is classified Uncertain significance in BBS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-01). AlphaMissense: ambiguous (0.4414); Very rare (popmax 0.00446%, eas); Associated with inherited retinal dystrophy.

What condition is associated with BBS2 p.Asn141Ile (c.422A>T)?

BBS2 p.Asn141Ile (c.422A>T) is associated with inherited retinal dystrophy (ClinVar).

How common is BBS2 p.Asn141Ile (c.422A>T) in the general population?

BBS2 p.Asn141Ile (c.422A>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about BBS2 p.Asn141Ile (c.422A>T)?

AlphaMissense predicts ambiguous (score 0.4414) — an in-silico prediction, not a clinical call.

BBS2 p.Asn141Ile

c.422A>T · rs144680278 · VCV3028364

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4414 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.4414	ambiguous
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -13.73	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	25.8	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 0.00446% East Asian · 2/44,870 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,461,854 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.Asn141Ile
Coding: c.422A>T
MANE Select: NM_031885
dbSNP: rs144680278
Type: single nucleotide variant
Location: chr16:56511208 (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

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

Similar variants

BBS2 p.Asn141Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BBS2 c.941-2A>C Pathogenic ★★ same condition
BBS2 p.Arg189Ter Pathogenic ★★ same condition
BBS2 p.Arg216Ter Pathogenic ★★ same condition
BBS2 p.Arg234Ter Pathogenic ★★ same condition
BBS2 p.Arg272Ter Pathogenic ★★ same condition
BBS2 p.Arg275Ter Pathogenic/Likely pathogenic ★★ same condition
BBS2 p.Arg315Gln Pathogenic/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-asn141ile (accessed [today's date]).

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