Is PSMB8 p.Ala92Pro (c.274G>C) pathogenic?

PSMB8 p.Ala92Pro (c.274G>C) is classified Uncertain significance in PSMB8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-11). AlphaMissense: likely pathogenic (0.9397); Absent from gnomAD v4.1; Associated with proteosome-associated autoinflammatory syndrome.

What condition is associated with PSMB8 p.Ala92Pro (c.274G>C)?

PSMB8 p.Ala92Pro (c.274G>C) is associated with proteosome-associated autoinflammatory syndrome (ClinVar).

How common is PSMB8 p.Ala92Pro (c.274G>C) in the general population?

PSMB8 p.Ala92Pro (c.274G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PSMB8 p.Ala92Pro (c.274G>C)?

AlphaMissense predicts likely pathogenic (score 0.9397) — an in-silico prediction, not a clinical call.

PSMB8 p.Ala92Pro

Q: How is Proteasome-associated autoinflammatory syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.274G>C · rs751107274 · VCV2109309

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9397 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

proteosome-associated autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.9397	likely pathogenic · top 10% in PSMB8
REVEL	0.634	indeterminate
SaProt	LLR -13.74	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 3,034 bp · p 0.22 · regional, not allelic
Overall
CADD	30.0	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: PSMB8
Protein: p.Ala92Pro
Coding: c.274G>C
MANE Select: NM_148919
dbSNP: rs751107274
Type: single nucleotide variant
Location: chr6:32842963 (GRCh38)
Gene constraint: LOEUF 0.849 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.28 · 22 PDB
Residue 92: a β-strand

Full PSMB8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

proteosome-associated autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Proteasome-associated autoinflammatory syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

PSMB8 p.Cys135Ter Pathogenic/Likely pathogenic ★★ same condition
PSMB8 p.Gln161Ter Pathogenic/Likely pathogenic ★★ same condition
PSMB8 p.Thr75Met Pathogenic ★★ same condition
PSMB8 p.Ala224Ser Uncertain significance ★★ ⚠ same condition
PSMB8 p.Arg192Trp Uncertain significance ★★ ⚠ same condition
PSMB8 p.Arg272Trp Uncertain significance ★★ ⚠ same condition
PSMB8 p.Asn157Ser Uncertain significance ★★ ⚠ same condition
PSMB8 p.Gly182Arg 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/psmb8-p-ala92pro (accessed [today's date]).

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