# NM_006391.3(IPO7):c.738A>C (p.Gln246His)

https://sugi.bio/variant/ipo7-p-gln246his

## Summary

**IPO7 p.Gln246His (c.738A>C)** is classified **Uncertain significance** in IPO7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely benign (0.1561); Very rare (popmax 0.00501%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00501%, amr)

## For patients & families {#patients}

This is a change in the IPO7 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 | [IPO7](https://sugi.bio/atlas/gene/IPO7/) |
| Protein change (HGVS p.) | p.Gln246His |
| Coding change (HGVS c.) | c.738A>C |
| MANE Select transcript | [NM_006391](https://www.ncbi.nlm.nih.gov/nuccore/NM_006391) |
| Variant type | single nucleotide variant |
| Location | chr11:9420422-9420422 (GRCh38) |
| ClinVar | [VCV4039195](https://www.ncbi.nlm.nih.gov/clinvar/variation/4039195/) |

**All HGVS expressions:** `NC_000011.10:g.9420422A>C`, `NC_000011.9:g.9441969A>C`, `NM_006391.3:c.738A>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1561)
- REVEL 0.283 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.386 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.462, GERP 1.14, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.2**. 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 0.93** across the covering region of the MANE Select transcript (9,408,506–9,423,054), spanning 14,548 bp. Chi-square p 0.24. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>G, Δ0.26 acceptor gain), 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 **0.00501%** (amr) · FAF95 0.00133% · FAF99 0.000668% · 3/59,926 in the highest group · 5/1,606,724 alleles overall — very rare (popmax 0.00501%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00501% | 19,975 |
| East Asian | 0.00223% | 44,866 |
| European (non-Finnish) | 8.51e-05% | 1,175,154 |

*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}

**IPO7** population constraint: LOEUF 0.138, pLI 1, missense-Z 2.8001. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.24, 70% of residues very-high.

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

*Describes the biological roles of IPO7 (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:** IPO7's established molecular role includes SMAD binding. In Reactome, IPO7 is annotated in disease pathway(s) including **Maturation of DENV proteins**.

**Disease mechanism (Reactome):** IPO7 loss or alteration is curated in [Maturation of DENV proteins](https://reactome.org/content/detail/R-HSA-9918432).

### Pathways affected {#pathways}

IPO7 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Maturation of DENV proteins](https://reactome.org/content/detail/R-HSA-9918432) | curated |

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

**Molecular function:** SMAD binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-11.

**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 | 2025-06-11 |

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

## Similar variants {#similar}

Related IPO7 variant pages (same residue, condition, or type): [IPO7 p.Ala363Gly](/variant/ipo7-p-ala363gly), [IPO7 p.Ala74Ser](/variant/ipo7-p-ala74ser), [IPO7 p.Ala764Gly](/variant/ipo7-p-ala764gly), [IPO7 p.Ala786Gly](/variant/ipo7-p-ala786gly), [IPO7 p.Ala843Ser](/variant/ipo7-p-ala843ser), [IPO7 p.Ala923Gly](/variant/ipo7-p-ala923gly), [IPO7 p.Ala979Thr](/variant/ipo7-p-ala979thr), [IPO7 p.Arg125His](/variant/ipo7-p-arg125his).

### 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 4039195). 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.*