Is PSMC5 p.Pro320Arg (c.959C>G) pathogenic?

PSMC5 p.Pro320Arg (c.959C>G) is classified Pathogenic/Likely pathogenic in PSMC5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-29). AlphaMissense: likely pathogenic (0.9962); Absent from gnomAD v4.1; Associated with PSMC5-related Neurodevelopmental proteasomopathy.

How common is PSMC5 p.Pro320Arg (c.959C>G) in the general population?

PSMC5 p.Pro320Arg (c.959C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PSMC5 p.Pro320Arg (c.959C>G)?

AlphaMissense predicts likely pathogenic (score 0.9962) — an in-silico prediction, not a clinical call.

PSMC5 p.Pro320Arg

Q: What condition is associated with PSMC5 p.Pro320Arg (c.959C>G)?

PSMC5 p.Pro320Arg (c.959C>G) is associated with PSMC5-related Neurodevelopmental proteasomopathy, neurodevelopmental disorder (ClinVar).

c.959C>G · VCV3899901

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9962 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PSMC5-related Neurodevelopmental proteasomopathy

Computational evidence

Protein change
AlphaMissense	0.9962	likely pathogenic ✓ concordant with ClinVar
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -15.48	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 2.4, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 1,550 bp · p 9.4e-31 · regional, not allelic
Overall
CADD	32.0	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

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: PSMC5
Protein: p.Pro320Arg
Coding: c.959C>G
MANE Select: NM_002805
Type: single nucleotide variant
Location: chr17:63831415 (GRCh38)
Gene constraint: LOEUF 0.386 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.47 · 140 PDB
Residue 320: the 'may mediate interaction with prpf9' region; an α-helix

Full PSMC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PSMC5-related Neurodevelopmental proteasomopathy

Also linked: neurodevelopmental disorder

Similar variants

PSMC5 p.Pro320His Uncertain significance ★ ⚠ same residue
PSMC5 p.Met80Val Uncertain significance ★ ⚠ same condition
PSMC5 p.Asp394fs Conflicting classifications of pathogenicity ★ ⚠ same condition
PSMC5 p.Lys393del Uncertain significance ★ same condition
PSMC5 c.264+9A>G Benign ★★ same type
PSMC5 c.97-8T>C Benign ★★ same type
PSMC5 p.Leu219= Benign ★★ same type
PSMC5 p.Leu280= Benign ★★ 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/psmc5-p-pro320arg (accessed [today's date]).

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