Is PSMB8 p.Ser242Phe (c.725C>T) pathogenic?

PSMB8 p.Ser242Phe (c.725C>T) is classified Uncertain significance in PSMB8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-12). AlphaMissense: likely pathogenic (0.987); Absent from gnomAD v4.1.

How common is PSMB8 p.Ser242Phe (c.725C>T) in the general population?

PSMB8 p.Ser242Phe (c.725C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PSMB8 p.Ser242Phe (c.725C>T)?

AlphaMissense predicts likely pathogenic (score 0.987) — an in-silico prediction, not a clinical call.

PSMB8 p.Ser242Phe

c.725C>T · VCV4974399

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.987	likely pathogenic · top 1% in PSMB8
REVEL	0.721	pathogenic-leaning
SaProt	LLR -16.56	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 3,034 bp · p 0.22 · regional, not allelic
Overall
CADD	33.0	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.Ser242Phe
Coding: c.725C>T
MANE Select: NM_148919
Type: single nucleotide variant
Location: chr6:32841548 (GRCh38)
Gene constraint: LOEUF 0.849 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.28 · 22 PDB

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

Similar variants

PSMB8 p.Ser242Pro Uncertain significance ★ ⚠ same residue
PSMB8 p.Cys135Ter Pathogenic/Likely pathogenic ★★ same type
PSMB8 p.Gln161Ter Pathogenic/Likely pathogenic ★★ same type
PSMB8 p.Thr75Met Pathogenic ★★ same type
PSMB8 p.Ala224Ser Uncertain significance ★★ ⚠ same type
PSMB8 p.Ala77Thr Uncertain significance ★★ same type
PSMB8 p.Arg129Cys Uncertain significance ★★ same type
PSMB8 p.Arg129His Uncertain significance ★★ same type

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-ser242phe (accessed [today's date]).

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