Is BBS5 p.Trp8Arg (c.22T>C) pathogenic?

BBS5 p.Trp8Arg (c.22T>C) is classified Uncertain significance in BBS5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-12). AlphaMissense: likely pathogenic (0.992); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with BBS5 p.Trp8Arg (c.22T>C)?

BBS5 p.Trp8Arg (c.22T>C) is associated with Inborn genetic diseases (ClinVar).

How common is BBS5 p.Trp8Arg (c.22T>C) in the general population?

BBS5 p.Trp8Arg (c.22T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about BBS5 p.Trp8Arg (c.22T>C)?

AlphaMissense predicts likely pathogenic (score 0.992) — an in-silico prediction, not a clinical call.

BBS5 p.Trp8Arg

c.22T>C · VCV3822154

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.992	likely pathogenic · top 6% in BBS5
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -12.18	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 25 kb · p 0.023 · regional, not allelic
Overall
CADD	28.8	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

Grpmax group 0.00133% African / African-American · 1/74,930 alleles

Overall 0.000657% 1/152,186 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: BBS5
Protein: p.Trp8Arg
Coding: c.22T>C
MANE Select: NM_152384
Type: single nucleotide variant
Location: chr2:169479575 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.87 · 1 PDB

Full BBS5 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

BBS5 p.Trp8Ter Pathogenic/Likely pathogenic ★★ same residue
BBS5 p.Trp8Cys Uncertain significance ★ ⚠ same residue
BBS5 p.Arg11Gln Uncertain significance ★★ ⚠ same condition
BBS5 p.Arg312His Uncertain significance ★★ ⚠ same condition
BBS5 p.Asn74Thr Uncertain significance ★★ ⚠ same condition
BBS5 p.Cys101Tyr Uncertain significance ★★ ⚠ same condition
BBS5 p.Gly45Arg Uncertain significance ★★ ⚠ same condition
BBS5 p.Phe299Ser 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/bbs5-p-trp8arg (accessed [today's date]).

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