# NM_002803.4(PSMC2):c.1192A>C (p.Arg398=)

https://sugi.bio/variant/psmc2-p-arg398

## Summary

**PSMC2 p.Arg398= (c.1192A>C)** is classified **Likely benign** in PSMC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-01). Ultra-rare (popmax 0.0214%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs373150287 · 1 submitter · ultra-rare (popmax 0.0214%, nfe)

## For patients & families {#patients}

This is a change in the PSMC2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PSMC2](https://sugi.bio/atlas/gene/PSMC2/) |
| Protein change (HGVS p.) | p.Arg398= |
| Coding change (HGVS c.) | c.1192A>C |
| MANE Select transcript | [NM_002803](https://www.ncbi.nlm.nih.gov/nuccore/NM_002803) |
| dbSNP | [rs373150287](https://www.ncbi.nlm.nih.gov/snp/rs373150287/) |
| Variant type | single nucleotide variant |
| Location | chr7:103367944-103367944 (GRCh38) |
| ClinVar | [VCV2657888](https://www.ncbi.nlm.nih.gov/clinvar/variation/2657888/) |

**All HGVS expressions:** `NC_000007.13:g.103008391A>C`, `NC_000007.14:g.103367944A>C`, `NG_023055.1:g.83234T>G`, `NM_001321787.2:c.1945+8864T>G`, `NM_002803.4:c.1192A>C`, `NM_206883.3:c.2041+8864T>G`, `NM_206884.3:c.1515-15018T>G`, `NM_206885.3:c.972-15018T>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 6.755, GERP 0.709, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 10.91**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0214%** (nfe) · FAF95 0.0193% · FAF99 0.0184% · 253/1,180,036 in the highest group · 273/1,614,036 alleles overall — ultra-rare (popmax 0.0214%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0214% | 4,664 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0135% | 7,402 |
| Finnish (not grpmax-eligible) | 0.0109% | 9,146 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,415 |
| African / African-American | 0.00267% | 37,457 |
| Admixed American | 0.00167% | 59,992 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**PSMC2** population constraint: LOEUF 0.274, pLI 1, missense-Z 4.6323. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **398** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 80.73, 21% of residues very-high.

**139 experimental structure(s)** (PDB): [5GJQ](https://www.rcsb.org/structure/5GJQ), [5GJR](https://www.rcsb.org/structure/5GJR), [5L4G](https://www.rcsb.org/structure/5L4G), [5LN3](https://www.rcsb.org/structure/5LN3), [5M32](https://www.rcsb.org/structure/5M32), [5T0C](https://www.rcsb.org/structure/5T0C).

## What this gene does {#gene-function}

*Describes the biological roles of PSMC2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** PSMC2's established molecular role includes proteasome-activating activity. In Reactome, PSMC2 is annotated in disease pathway(s) including **Defective CFTR causes cystic fibrosis**, **Hh mutants are degraded by ERAD**.

**Disease mechanism (Reactome):** PSMC2 loss or alteration is curated in [Defective CFTR causes cystic fibrosis](https://reactome.org/content/detail/R-HSA-5678895), [Hh mutants are degraded by ERAD](https://reactome.org/content/detail/R-HSA-5362768), [Vif-mediated degradation of APOBEC3G](https://reactome.org/content/detail/R-HSA-180585).

### Pathways affected {#pathways}

PSMC2 participates in **69 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective CFTR causes cystic fibrosis](https://reactome.org/content/detail/R-HSA-5678895) | curated |
| ⚕ [Hh mutants are degraded by ERAD](https://reactome.org/content/detail/R-HSA-5362768) | curated |
| ⚕ [Vif-mediated degradation of APOBEC3G](https://reactome.org/content/detail/R-HSA-180585) | curated |
| ⚕ [Vpu mediated degradation of CD4](https://reactome.org/content/detail/R-HSA-180534) | curated |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |
| [AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9931269) | curated |
| [APC/C:Cdc20 mediated degradation of Securin](https://reactome.org/content/detail/R-HSA-174154) | curated |
| [APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1](https://reactome.org/content/detail/R-HSA-174178) | curated |
| [AUF1 (hnRNP D0) binds and destabilizes mRNA](https://reactome.org/content/detail/R-HSA-450408) | curated |
| [Activation of NF-kappaB in B cells](https://reactome.org/content/detail/R-HSA-1169091) | curated |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [Assembly of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68867) | curated |
| [Asymmetric localization of PCP proteins](https://reactome.org/content/detail/R-HSA-4608870) | curated |
| [Autodegradation of Cdh1 by Cdh1:APC/C](https://reactome.org/content/detail/R-HSA-174084) | curated |
| [Autodegradation of the E3 ubiquitin ligase COP1](https://reactome.org/content/detail/R-HSA-349425) | curated |
| [CDK-mediated phosphorylation and removal of Cdc6](https://reactome.org/content/detail/R-HSA-69017) | curated |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | curated |
| [Cdc20:Phospho-APC/C mediated degradation of Cyclin A](https://reactome.org/content/detail/R-HSA-174184) | curated |
| [Cross-presentation of soluble exogenous antigens (endosomes)](https://reactome.org/content/detail/R-HSA-1236978) | curated |
| [Dectin-1 mediated noncanonical NF-kB signaling](https://reactome.org/content/detail/R-HSA-5607761) | curated |
| [Degradation of AXIN](https://reactome.org/content/detail/R-HSA-4641257) | curated |
| [Degradation of CDH1](https://reactome.org/content/detail/R-HSA-9766229) | curated |
| [Degradation of DVL](https://reactome.org/content/detail/R-HSA-4641258) | curated |
| [Degradation of GLI1 by the proteasome](https://reactome.org/content/detail/R-HSA-5610780) | curated |
| [Degradation of beta-catenin by the destruction complex](https://reactome.org/content/detail/R-HSA-195253) | curated |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | curated |
| [FBXL7 down-regulates AURKA during mitotic entry and in early mitosis](https://reactome.org/content/detail/R-HSA-8854050) | curated |
| [FCERI mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-2871837) | curated |
| [G2/M Checkpoints](https://reactome.org/content/detail/R-HSA-69481) | curated |
| [GLI3 is processed to GLI3R by the proteasome](https://reactome.org/content/detail/R-HSA-5610785) | curated |
| [GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2](https://reactome.org/content/detail/R-HSA-9762114) | curated |
| [GSK3B-mediated proteasomal degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9929356) | curated |
| [Hedgehog 'on' state](https://reactome.org/content/detail/R-HSA-5632684) | curated |
| [Hedgehog ligand biogenesis](https://reactome.org/content/detail/R-HSA-5358346) | curated |
| [Interleukin-1 signaling](https://reactome.org/content/detail/R-HSA-9020702) | curated |
| [KEAP1-NFE2L2 pathway](https://reactome.org/content/detail/R-HSA-9755511) | curated |
| [MAPK6/MAPK4 signaling](https://reactome.org/content/detail/R-HSA-5687128) | curated |
| [NIK-->noncanonical NF-kB signaling](https://reactome.org/content/detail/R-HSA-5676590) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [Negative Regulation of DNA Double Strand Break Response](https://reactome.org/content/detail/R-HSA-9974237) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Orc1 removal from chromatin](https://reactome.org/content/detail/R-HSA-68949) | curated |
| [Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha](https://reactome.org/content/detail/R-HSA-1234176) | curated |
| [RUNX1 regulates transcription of genes involved in differentiation of HSCs](https://reactome.org/content/detail/R-HSA-8939236) | curated |
| [Regulation of PTEN stability and activity](https://reactome.org/content/detail/R-HSA-8948751) | curated |
| [Regulation of RAS by GAPs](https://reactome.org/content/detail/R-HSA-5658442) | curated |
| [Regulation of RUNX3 expression and activity](https://reactome.org/content/detail/R-HSA-8941858) | curated |
| [Regulation of ornithine decarboxylase (ODC)](https://reactome.org/content/detail/R-HSA-350562) | curated |
| [SCF(Skp2)-mediated degradation of p27/p21](https://reactome.org/content/detail/R-HSA-187577) | curated |
| [SCF-beta-TrCP mediated degradation of Emi1](https://reactome.org/content/detail/R-HSA-174113) | curated |
| [SPOP-mediated proteasomal degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9929491) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |
| [TNFR2 non-canonical NF-kB pathway](https://reactome.org/content/detail/R-HSA-5668541) | curated |
| [The role of GTSE1 in G2/M progression after G2 checkpoint](https://reactome.org/content/detail/R-HSA-8852276) | curated |
| [UCH proteinases](https://reactome.org/content/detail/R-HSA-5689603) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A](https://reactome.org/content/detail/R-HSA-69601) | curated |
| [Ubiquitin-dependent degradation of Cyclin D](https://reactome.org/content/detail/R-HSA-75815) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | electronic |
| [Degradation of CRY and PER proteins](https://reactome.org/content/detail/R-HSA-9932298) | electronic |
| [Degradation of GLI2 by the proteasome](https://reactome.org/content/detail/R-HSA-5610783) | electronic |
| [ER-Phagosome pathway](https://reactome.org/content/detail/R-HSA-1236974) | electronic |
| [Negative regulation of NOTCH4 signaling](https://reactome.org/content/detail/R-HSA-9604323) | electronic |
| [Proteasome assembly](https://reactome.org/content/detail/R-HSA-9907900) | electronic |
| [Regulation of RUNX2 expression and activity](https://reactome.org/content/detail/R-HSA-8939902) | electronic |
| [Regulation of activated PAK-2p34 by proteasome mediated degradation](https://reactome.org/content/detail/R-HSA-211733) | electronic |
| [Regulation of expression of SLITs and ROBOs](https://reactome.org/content/detail/R-HSA-9010553) | electronic |
| [Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide](https://reactome.org/content/detail/R-HSA-9954709) | electronic |
| [Somitogenesis](https://reactome.org/content/detail/R-HSA-9824272) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** proteasome-activating activity.

**Biological process:** osteoblast differentiation, ubiquitin-dependent protein catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-04-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-04-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related PSMC2 variant pages (same residue, condition, or type): [PSMC2 p.Ala235Val](/variant/psmc2-p-ala235val), [PSMC2 p.Ala24Val](/variant/psmc2-p-ala24val), [PSMC2 p.Ala412Ser](/variant/psmc2-p-ala412ser), [PSMC2 p.Ala7Ser](/variant/psmc2-p-ala7ser), [PSMC2 p.Arg360Cys](/variant/psmc2-p-arg360cys), [PSMC2 p.Arg375Gln](/variant/psmc2-p-arg375gln), [PSMC2 p.Asp347Glu](/variant/psmc2-p-asp347glu), [PSMC2 p.Gln47His](/variant/psmc2-p-gln47his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2657888). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*