# NM_006503.4(PSMC4):c.514A>G (p.Ile172Val)

https://sugi.bio/variant/psmc4-p-ile172val

## Summary

**PSMC4 p.Ile172Val (c.514A>G)** is classified **Uncertain significance** in PSMC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: likely benign (0.0744); Ultra-rare (popmax 0.0187%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs373413671 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0187%, afr)

## For patients & families {#patients}

This is a change in the PSMC4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [PSMC4](https://sugi.bio/atlas/gene/PSMC4/) |
| Protein change (HGVS p.) | p.Ile172Val |
| Coding change (HGVS c.) | c.514A>G |
| MANE Select transcript | [NM_006503](https://www.ncbi.nlm.nih.gov/nuccore/NM_006503) |
| dbSNP | [rs373413671](https://www.ncbi.nlm.nih.gov/snp/rs373413671/) |
| Variant type | single nucleotide variant |
| Location | chr19:39974568-39974568 (GRCh38) |
| ClinVar | [VCV3220409](https://www.ncbi.nlm.nih.gov/clinvar/variation/3220409/) |

**All HGVS expressions:** `NC_000019.10:g.39974568A>G`, `NC_000019.9:g.40480475A>G`, `NM_006503.4:c.514A>G`, `NM_153001.3:c.421A>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0744)
- REVEL 0.37 (indeterminate)
- SaProt LLR -7.593 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 11.201, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.6**. 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.*
- Regional missense constraint: **o/e 0.47** across the covering region of the MANE Select transcript (39,972,195–39,979,847), spanning 7,652 bp. Chi-square p 2e-18. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for PSMC4 (523 scored positions, the nearest 17 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0187%** (afr) · FAF95 0.0112% · FAF99 0.00905% · 14/74,920 in the highest group · 21/1,613,994 alleles overall — ultra-rare (popmax 0.0187%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0187% | 5,351 |
| Admixed American | 0.005% | 20,001 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,828 |
| South Asian | 0.0011% | 91,088 |

*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}

**PSMC4** population constraint: LOEUF 0.407, pLI 0.99984, missense-Z 4.8513. *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 **172** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 80.33, 23% of residues very-high.

**140 experimental structure(s)** (PDB): [2DVW](https://www.rcsb.org/structure/2DVW), [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).

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

*Describes the biological roles of PSMC4 (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:** PSMC4 participates in disease-associated pathways. In Reactome, PSMC4 is annotated in disease pathway(s) including **Defective CFTR causes cystic fibrosis**, **Hh mutants are degraded by ERAD**.

**Disease mechanism (Reactome):** PSMC4 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}

PSMC4 participates in **68 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 |
| [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 |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-24.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-24 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related PSMC4 variant pages (same residue, condition, or type): [PSMC4 p.Arg178Gln](/variant/psmc4-p-arg178gln), [PSMC4 p.Arg252His](/variant/psmc4-p-arg252his), [PSMC4 p.Arg43His](/variant/psmc4-p-arg43his), [PSMC4 p.Asp13His](/variant/psmc4-p-asp13his), [PSMC4 p.Asp161Gly](/variant/psmc4-p-asp161gly), [PSMC4 p.Asp197Asn](/variant/psmc4-p-asp197asn), [PSMC4 p.Gln24His](/variant/psmc4-p-gln24his), [PSMC4 p.Glu33Lys](/variant/psmc4-p-glu33lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3220409). 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.*