Is BBS9 p.Pro176Ser (c.526C>T) pathogenic?

BBS9 p.Pro176Ser (c.526C>T) is classified Uncertain significance in BBS9 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-01-01). AlphaMissense: ambiguous (0.344); Absent from gnomAD v4.1; Associated with inherited retinal dystrophy.

What condition is associated with BBS9 p.Pro176Ser (c.526C>T)?

BBS9 p.Pro176Ser (c.526C>T) is associated with inherited retinal dystrophy (ClinVar).

How common is BBS9 p.Pro176Ser (c.526C>T) in the general population?

BBS9 p.Pro176Ser (c.526C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BBS9 p.Pro176Ser (c.526C>T)?

AlphaMissense predicts ambiguous (score 0.344) — an in-silico prediction, not a clinical call.

BBS9 p.Pro176Ser

c.526C>T · VCV3249317

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.344 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.344	ambiguous
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -11.37	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 459 kb · p 0.062 · regional, not allelic
Overall
CADD	26.5	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: BBS9
Protein: p.Pro176Ser
Coding: c.526C>T
MANE Select: NM_198428
Type: single nucleotide variant
Location: chr7:33257319 (GRCh38)
Gene constraint: LOEUF 0.959 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.41 · 2 PDB
Residue 176: the 'seven-bladed beta-propeller' region

Full BBS9 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

BBS9 p.Pro176Arg Uncertain significance ★★ ⚠ same residue
BBS9 p.Pro176= Likely benign ★ same residue
BBS9 c.263+1G>T Pathogenic ★★ same condition
BBS9 p.Arg374Ter Pathogenic/Likely pathogenic ★★ same condition
BBS9 p.Asp830Asn Uncertain significance ★★ ⚠ same condition
BBS9 p.Val371Ala Uncertain significance ★★ ⚠ same condition
BBS9 p.Glu753Val Conflicting classifications of pathogenicity ★ same condition
BBS9 p.Ser785Leu 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/bbs9-p-pro176ser (accessed [today's date]).

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