# NM_006390.4(IPO8):c.2589C>T (p.Pro863=)

https://sugi.bio/variant/ipo8-p-pro863

## Summary

**IPO8 p.Pro863= (c.2589C>T)** is classified **Likely benign** in IPO8 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-26). Rare (popmax 0.173%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs143442160 · 1 submitter · rare (popmax 0.173%, afr)

## For patients & families {#patients}

This is a change in the IPO8 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 | [IPO8](https://sugi.bio/atlas/gene/IPO8/) |
| Protein change (HGVS p.) | p.Pro863= |
| Coding change (HGVS c.) | c.2589C>T |
| MANE Select transcript | [NM_006390](https://www.ncbi.nlm.nih.gov/nuccore/NM_006390) |
| dbSNP | [rs143442160](https://www.ncbi.nlm.nih.gov/snp/rs143442160/) |
| Variant type | single nucleotide variant |
| Location | chr12:30637088-30637088 (GRCh38) |
| ClinVar | [VCV716430](https://www.ncbi.nlm.nih.gov/clinvar/variation/716430/) |

**All HGVS expressions:** `NC_000012.11:g.30790022G>A`, `NC_000012.12:g.30637088G>A`, `NM_001190995.2:c.1974C>T`, `NM_006390.4:c.2589C>T`

## 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 0.96, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 7.015**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.25 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.173%** (afr) · FAF95 0.149% · FAF99 0.14% · 130/75,020 in the highest group · 140/1,613,934 alleles overall — rare (popmax 0.173%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.173% | 577 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,928 |
| Admixed American | 0.00333% | 30,003 |
| European (non-Finnish) | 8.48e-05% | 1,179,926 |

*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 **863** 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); a UniProt-annotated variant site (in viss; undetectable protein levels in patient's fibroblasts, although mrna levels seem unaffected).

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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-07-26.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2018-07-26 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## 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.Arg803Ter](/variant/ipo8-p-arg803ter), [IPO8 p.Trp259Ter](/variant/ipo8-p-trp259ter), [IPO8 p.Ala877Asp](/variant/ipo8-p-ala877asp), [IPO8 p.Ala941Val](/variant/ipo8-p-ala941val), [IPO8 p.Arg1002Trp](/variant/ipo8-p-arg1002trp), [IPO8 p.Arg884Gln](/variant/ipo8-p-arg884gln).

### 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 716430). 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.*