Is PSMC5 p.Pro320His (c.959C>A) pathogenic?

PSMC5 p.Pro320His (c.959C>A) is classified Uncertain significance in PSMC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-16). AlphaMissense: likely pathogenic (0.9974); Very rare (popmax 0.000678%, nfe).

How common is PSMC5 p.Pro320His (c.959C>A) in the general population?

PSMC5 p.Pro320His (c.959C>A) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about PSMC5 p.Pro320His (c.959C>A)?

AlphaMissense predicts likely pathogenic (score 0.9974) — an in-silico prediction, not a clinical call.

PSMC5 p.Pro320His

c.959C>A · VCV3911851

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9974	likely pathogenic
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -15.91	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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

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

Grpmax group 0.000678% European (non-Finnish) · 8/1,179,938 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,918 alleles · very rare exomes 8/1,461,626 · genomes 0/152,292 · joint denominator

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: PSMC5
Protein: p.Pro320His
Coding: c.959C>A
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

Similar variants

PSMC5 p.Pro320Arg Pathogenic/Likely pathogenic ★★ same residue
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
PSMC5 p.Arg325Trp Pathogenic ★ same type
PSMC5 p.Met368Thr Likely pathogenic ★ ⚠ same type
PSMC5 c.1081-2A>G 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/psmc5-p-pro320his (accessed [today's date]).

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