Is BBS4 p.Ser291Arg (c.871A>C) pathogenic?

BBS4 p.Ser291Arg (c.871A>C) is classified Uncertain significance in BBS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-13). AlphaMissense: likely pathogenic (0.9977); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with BBS4 p.Ser291Arg (c.871A>C)?

BBS4 p.Ser291Arg (c.871A>C) is associated with Inborn genetic diseases (ClinVar).

How common is BBS4 p.Ser291Arg (c.871A>C) in the general population?

BBS4 p.Ser291Arg (c.871A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BBS4 p.Ser291Arg (c.871A>C)?

AlphaMissense predicts likely pathogenic (score 0.9977) — an in-silico prediction, not a clinical call.

BBS4 p.Ser291Arg

c.871A>C · rs2065823812 · VCV2266325

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9977 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9977	likely pathogenic · top 2% in BBS4
REVEL	0.739	pathogenic-leaning
SaProt	LLR -14.88	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 9.4	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	27.3	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

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.Ser291Arg
Coding: c.871A>C
MANE Select: NM_033028
dbSNP: rs2065823812
Type: single nucleotide variant
Location: chr15:72731561 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 291: the 'interaction with pcm1' region

Full BBS4 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

BBS4 p.Ser291Gly Uncertain significance ★ ⚠ same residue
BBS4 p.Ala391Thr Uncertain significance ★★ ⚠ same condition
BBS4 p.Ala477Val Uncertain significance ★★ ⚠ same condition
BBS4 p.Asp168Asn Uncertain significance ★★ same condition
BBS4 p.Glu355Gln Uncertain significance ★★ ⚠ same condition
BBS4 p.Ile146Thr Uncertain significance ★★ ⚠ same condition
BBS4 p.Leu148Gln Uncertain significance ★★ ⚠ same condition
BBS4 p.Leu343Ile 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/bbs4-p-ser291arg (accessed [today's date]).

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