# NM_006390.4(IPO8):c.1000dup (p.Val334fs)

https://sugi.bio/variant/ipo8-p-val334fs

## Summary

**IPO8 p.Val334fs (c.1000dup)** is classified **Pathogenic** in IPO8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-18). No gnomAD frequency available for this variant; Associated with IPO8-related aortopathy.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2136158926 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the IPO8 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to IPO8-related aortopathy.

*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 | [IPO8](https://sugi.bio/atlas/gene/IPO8/) |
| Protein change (HGVS p.) | p.Val334fs |
| Coding change (HGVS c.) | c.1000dup |
| MANE Select transcript | [NM_006390](https://www.ncbi.nlm.nih.gov/nuccore/NM_006390) |
| dbSNP | [rs2136158926](https://www.ncbi.nlm.nih.gov/snp/rs2136158926/) |
| Variant type | Duplication |
| Location | chr12:30671005-30671006 (GRCh38) |
| ClinVar | [VCV1047910](https://www.ncbi.nlm.nih.gov/clinvar/variation/1047910/) |

**All HGVS expressions:** `NC_000012.11:g.30823943dup`, `NC_000012.12:g.30671009dup`, `NM_001190995.2:c.385dup`, `NM_006390.4:c.1000dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.139, GERP 2.03, phastCons 0.997 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.575, pLI 0.15221. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 25**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**IPO8** population constraint: LOEUF 0.575, pLI 0.15221, missense-Z 2.2699. *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 **334** lies in a UniProt-annotated variant site (in viss; undetectable protein levels in either patient's fibroblasts or patient's epstein-barr virus-immortalized b cell lines); a UniProt-annotated variant site (in viss).

AlphaFold model confidence (whole protein): pLDDT 87.59, 72% of residues very-high.

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

*Describes the biological roles of IPO8 (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.*


### Pathways affected {#pathways}

IPO8 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Transcriptional regulation by small RNAs](https://reactome.org/content/detail/R-HSA-5578749) | curated |

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-03-18.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Centre of Medical Genetics, University of Antwerp | Pathogenic | criteria provided, single submitter | research | 2021-03-18 |

## Associated conditions {#conditions}

[IPO8-related aortopathy](https://sugi.bio/atlas/disease/ipo8-related-aortopathy/).

**Reported phenotype names (ClinVar):** IPO8-related aortopathy.

## Similar variants {#similar}

Related IPO8 variant pages (same residue, condition, or type): [IPO8 c.2900-1G>A](/variant/ipo8-c-2900-minus-1g-a), [IPO8 p.Arg474Ter](/variant/ipo8-p-arg474ter), [IPO8 p.Trp259Ter](/variant/ipo8-p-trp259ter), [IPO8 c.1428+5G>A](/variant/ipo8-c-1428-plus-5g-a), [IPO8 p.Arg971Ter](/variant/ipo8-p-arg971ter), [IPO8 p.Leu783fs](/variant/ipo8-p-leu783fs), [IPO8 p.Leu866fs](/variant/ipo8-p-leu866fs), [IPO8 p.Trp229Ter](/variant/ipo8-p-trp229ter).

### 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 1047910). 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.*