Is BBS4 p.Arg109Thr (c.326G>C) pathogenic?

BBS4 p.Arg109Thr (c.326G>C) is classified Uncertain significance in BBS4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-05-08). AlphaMissense: likely pathogenic (0.99); Absent from gnomAD v4.1; Associated with BBS4-related disorder.

What condition is associated with BBS4 p.Arg109Thr (c.326G>C)?

BBS4 p.Arg109Thr (c.326G>C) is associated with BBS4-related disorder (ClinVar).

How common is BBS4 p.Arg109Thr (c.326G>C) in the general population?

BBS4 p.Arg109Thr (c.326G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BBS4 p.Arg109Thr (c.326G>C)?

AlphaMissense predicts likely pathogenic (score 0.99) — an in-silico prediction, not a clinical call.

BBS4 p.Arg109Thr

c.326G>C · VCV3349337

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.99 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

BBS4-related disorder

Computational evidence

Protein change
AlphaMissense	0.99	likely pathogenic · top 5% in BBS4
REVEL	0.496	indeterminate
SaProt	LLR -15.40	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	29.5	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.Arg109Thr
Coding: c.326G>C
MANE Select: NM_033028
Type: single nucleotide variant
Location: chr15:72715396 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 109: the 'interaction with pcm1' region

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

Disease context

BBS4-related disorder

Similar variants

BBS4 p.Arg109Ser Uncertain significance ★ ⚠ same residue
BBS4 p.Arg109= Likely benign ★ same residue
BBS4 c.1248+2T>C Pathogenic/Likely pathogenic ★★ same condition
BBS4 c.157-3C>G Pathogenic ★★ same condition
BBS4 c.220+1G>C Pathogenic ★★ same condition
BBS4 c.24+1G>A Likely pathogenic ★★ same condition
BBS4 c.332+8T>C Pathogenic/Likely pathogenic ★★ same condition
BBS4 c.712-1G>A 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/bbs4-p-arg109thr (accessed [today's date]).

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