Is BBS4 p.Ser269Cys (c.805A>T) pathogenic?

BBS4 p.Ser269Cys (c.805A>T) is classified Uncertain significance in BBS4 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely benign (0.1937); Absent from gnomAD v4.1.

How common is BBS4 p.Ser269Cys (c.805A>T) in the general population?

BBS4 p.Ser269Cys (c.805A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BBS4 p.Ser269Cys (c.805A>T)?

AlphaMissense predicts likely benign (score 0.1937) — an in-silico prediction, not a clinical call.

BBS4 p.Ser269Cys

c.805A>T · rs917260700 · VCV1050687

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1937 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1937	likely benign
REVEL	0.724	pathogenic-leaning
SaProt	LLR -5.64	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 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	27.9	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

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: BBS4
Protein: p.Ser269Cys
Coding: c.805A>T
MANE Select: NM_033028
dbSNP: rs917260700
Type: single nucleotide variant
Location: chr15:72731398 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 269: the 'interaction with pcm1' region

Full BBS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BBS4 c.1106+2T>A Pathogenic/Likely pathogenic ★★ same type
BBS4 c.1248+1G>A Pathogenic/Likely pathogenic ★★ same type
BBS4 c.1248+1G>T Pathogenic ★★ same type
BBS4 c.1248+2T>C Pathogenic/Likely pathogenic ★★ same type
BBS4 c.1249-2A>C Likely pathogenic ★★ same type
BBS4 c.157-2A>G Pathogenic ★★ same type
BBS4 c.157-3C>G Pathogenic ★★ same type
BBS4 c.220+1G>C 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/bbs4-p-ser269cys (accessed [today's date]).

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