Is PSMB5 p.Phe185Leu (c.555C>G) pathogenic?

PSMB5 p.Phe185Leu (c.555C>G) is classified Uncertain significance in PSMB5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-14). AlphaMissense: likely pathogenic (0.9978); Very rare (popmax 0.00223%, eas).

How common is PSMB5 p.Phe185Leu (c.555C>G) in the general population?

PSMB5 p.Phe185Leu (c.555C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PSMB5 p.Phe185Leu (c.555C>G)?

AlphaMissense predicts likely pathogenic (score 0.9978) — an in-silico prediction, not a clinical call.

PSMB5 p.Phe185Leu

c.555C>G · VCV4526758

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9978	likely pathogenic · top 10% in PSMB5
REVEL	0.388	indeterminate
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 7,294 bp · p 0.13 · regional, not allelic
Overall
CADD	25.1	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

Grpmax group 0.00223% East Asian · 1/44,882 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00041% 6/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
European (non-Finnish)	0.000424%	236,003

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: PSMB5
Protein: p.Phe185Leu
Coding: c.555C>G
MANE Select: NM_002797
Type: single nucleotide variant
Location: chr14:23026326 (GRCh38)
Gene constraint: LOEUF 0.255 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.34 · 156 PDB
Residue 185: a β-strand

Full PSMB5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PSMB5 p.Ala119Gly Uncertain significance ★ ⚠ same type
PSMB5 p.Ala74Ser Uncertain significance ★ ⚠ same type
PSMB5 p.Arg120Gln Uncertain significance ★ ⚠ same type
PSMB5 p.Arg132Cys Uncertain significance ★ ⚠ same type
PSMB5 p.Arg132Pro Uncertain significance ★ ⚠ same type
PSMB5 p.Arg132Ser Uncertain significance ★ ⚠ same type
PSMB5 p.Arg216His Uncertain significance ★ ⚠ same type
PSMB5 p.Arg239Gln 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/psmb5-p-phe185leu (accessed [today's date]).

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