Is PSMB4 p.Arg8Pro (c.23G>C) pathogenic?

PSMB4 p.Arg8Pro (c.23G>C) is classified Uncertain significance in PSMB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). AlphaMissense: likely benign (0.0855); Very rare (popmax 0.00186%, nfe).

How common is PSMB4 p.Arg8Pro (c.23G>C) in the general population?

PSMB4 p.Arg8Pro (c.23G>C) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about PSMB4 p.Arg8Pro (c.23G>C)?

AlphaMissense predicts likely benign (score 0.0855) — an in-silico prediction, not a clinical call.

PSMB4 p.Arg8Pro

c.23G>C · rs1049463156 · VCV1368324

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0855 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0855	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -4.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -0.51, phastCons 0.98
Regional constraint	o/e 0.95	unconstrained · MANE · 2,238 bp · p 0.32 · regional, not allelic
Overall
CADD	18.74	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00186% European (non-Finnish) · 22/1,179,684 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 24/1,613,042 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00186%	53,622
Remaining individualsnot grpmax-eligible	0.0016%	62,438
African / African-American	0.00134%	74,850

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: PSMB4
Protein: p.Arg8Pro
Coding: c.23G>C
MANE Select: NM_002796
dbSNP: rs1049463156
Type: single nucleotide variant
Location: chr1:151399610 (GRCh38)
Gene constraint: LOEUF 0.659 · pLI 0.13 (gnomAD)
Structure: AlphaFold pLDDT 87.70 · 150 PDB

Full PSMB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PSMB4 p.Arg8Trp Uncertain significance ★ ⚠ same residue
PSMB4 c.-9G>A Uncertain significance ★★ same type
PSMB4 p.Ala17Ser Uncertain significance ★★ ⚠ same type
PSMB4 p.Arg211Cys Uncertain significance ★★ ⚠ same type
PSMB4 p.Asn230Asp Uncertain significance ★★ ⚠ same type
PSMB4 p.Asn230Ser Uncertain significance ★★ ⚠ same type
PSMB4 p.Asn83Ser Uncertain significance ★★ ⚠ same type
PSMB4 p.Asn92Lys 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/psmb4-p-arg8pro (accessed [today's date]).

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