Is PSMC4 p.Pro199Arg (c.596C>G) pathogenic?

PSMC4 p.Pro199Arg (c.596C>G) is classified Uncertain significance in PSMC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.9992); Very rare (popmax 0.000424%, nfe).

How common is PSMC4 p.Pro199Arg (c.596C>G) in the general population?

PSMC4 p.Pro199Arg (c.596C>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about PSMC4 p.Pro199Arg (c.596C>G)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

PSMC4 p.Pro199Arg

c.596C>G · VCV4573299

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic · top 10% in PSMC4
REVEL	0.811	moderately pathogenic-leaning
SaProt	LLR -14.96	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	phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 7,652 bp · p 2e-18 · regional, not allelic
Overall
CADD	27.3	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 0.000424% European (non-Finnish) · 5/1,180,034 alleles

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

Overall 0.000372% 6/1,614,064 alleles · very rare exomes 5/1,461,872 · genomes 1/152,192 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)grpmax	0.000424%	236,007

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PSMC4
Protein: p.Pro199Arg
Coding: c.596C>G
MANE Select: NM_006503
Type: single nucleotide variant
Location: chr19:39974751 (GRCh38)
Gene constraint: LOEUF 0.407 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.33 · 140 PDB
Residue 199: an α-helix

Full PSMC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PSMC4 p.Arg178Gln Uncertain significance ★ ⚠ same type
PSMC4 p.Arg252His Uncertain significance ★ ⚠ same type
PSMC4 p.Arg43His Uncertain significance ★ ⚠ same type
PSMC4 p.Asp13His Uncertain significance ★ ⚠ same type
PSMC4 p.Asp161Gly Uncertain significance ★ same type
PSMC4 p.Asp197Asn Uncertain significance ★ ⚠ same type
PSMC4 p.Gln24His Uncertain significance ★ ⚠ same type
PSMC4 p.Glu33Lys 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/psmc4-p-pro199arg (accessed [today's date]).

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