# NM_198449.3(EMB):c.538T>C (p.Cys180Arg)

https://sugi.bio/variant/emb-p-cys180arg

## Summary

**EMB p.Cys180Arg (c.538T>C)** is classified **Uncertain significance** in EMB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-19). AlphaMissense: likely pathogenic (0.9102); Ultra-rare (popmax 0.0166%, mid).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1249116610 · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0166%, mid)

## For patients & families {#patients}

This is a change in the EMB 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 | [EMB](https://sugi.bio/atlas/gene/EMB/) |
| Protein change (HGVS p.) | p.Cys180Arg |
| Coding change (HGVS c.) | c.538T>C |
| MANE Select transcript | [NM_003400](https://www.ncbi.nlm.nih.gov/nuccore/NM_003400) (variant reported on NM_198449) |
| dbSNP | [rs1249116610](https://www.ncbi.nlm.nih.gov/snp/rs1249116610/) |
| Variant type | single nucleotide variant |
| Location | chr5:50405787-50405787 (GRCh38) |
| ClinVar | [VCV3088540](https://www.ncbi.nlm.nih.gov/clinvar/variation/3088540/) |

**All HGVS expressions:** `NC_000005.10:g.50405787A>G`, `NC_000005.9:g.49701621A>G`, `NM_198449.3:c.538T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9102)
- REVEL 0.644 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.301 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 8.891, GERP 1.66, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.8**. 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 (A>C, Δ0.97 donor 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 **0.0166%** (mid) · FAF95 0.00327% · FAF99 0.00295% · 1/6,040 in the highest group · 55/1,606,932 alleles overall — ultra-rare (popmax 0.0166%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0166% | 6,040 |
| Remaining individuals (not grpmax-eligible) | 0.00644% | 15,521 |
| European (non-Finnish) | 0.00425% | 23,535 |

*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.*

## Protein context {#protein}

Residue **180** lies in the 'necessary for htlv-1 rex-mediated mrna export' region.

AlphaFold model confidence (whole protein): pLDDT 91.62, 79% of residues very-high.

**19 experimental structure(s)** (PDB): [1W9C](https://www.rcsb.org/structure/1W9C), [2L1L](https://www.rcsb.org/structure/2L1L), [3GB8](https://www.rcsb.org/structure/3GB8), [4BSM](https://www.rcsb.org/structure/4BSM), [4BSN](https://www.rcsb.org/structure/4BSN), [5DIS](https://www.rcsb.org/structure/5DIS).

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

*Describes the biological roles of EMB (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:** EMB's established molecular role includes nuclear export signal receptor activity. p.Cys180Arg falls in the necessary for htlv-1 rex-mediated mrna export region. In Reactome, EMB is annotated in disease pathway(s) including **Maturation of DENV proteins**, **Maturation of hRSV A proteins**.

**Disease mechanism (Reactome):** EMB loss or alteration is curated in [Maturation of DENV proteins](https://reactome.org/content/detail/R-HSA-9918432), [Maturation of hRSV A proteins](https://reactome.org/content/detail/R-HSA-9828806), [NEP/NS2 Interacts with the Cellular Export Machinery](https://reactome.org/content/detail/R-HSA-168333).

### Pathways affected {#pathways}

EMB participates in **19 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Maturation of DENV proteins](https://reactome.org/content/detail/R-HSA-9918432) | curated |
| ⚕ [Maturation of hRSV A proteins](https://reactome.org/content/detail/R-HSA-9828806) | curated |
| ⚕ [NEP/NS2 Interacts with the Cellular Export Machinery](https://reactome.org/content/detail/R-HSA-168333) | curated |
| ⚕ [Rev-mediated nuclear export of HIV RNA](https://reactome.org/content/detail/R-HSA-165054) | curated |
| [Amplification  of signal from unattached  kinetochores via a MAD2  inhibitory signal](https://reactome.org/content/detail/R-HSA-141444) | curated |
| [Cyclin A/B1/B2 associated events during G2/M transition](https://reactome.org/content/detail/R-HSA-69273) | curated |
| [Deactivation of the beta-catenin transactivating complex](https://reactome.org/content/detail/R-HSA-3769402) | curated |
| [EML4 and NUDC in mitotic spindle formation](https://reactome.org/content/detail/R-HSA-9648025) | curated |
| [Estrogen-dependent nuclear events downstream of ESR-membrane signaling](https://reactome.org/content/detail/R-HSA-9634638) | curated |
| [Heme signaling](https://reactome.org/content/detail/R-HSA-9707616) | curated |
| [HuR (ELAVL1) binds and stabilizes mRNA](https://reactome.org/content/detail/R-HSA-450520) | curated |
| [MAPK6/MAPK4 signaling](https://reactome.org/content/detail/R-HSA-5687128) | curated |
| [Mitotic Prometaphase](https://reactome.org/content/detail/R-HSA-68877) | curated |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | curated |
| [Resolution of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2500257) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | curated |
| [Downregulation of TGF-beta receptor signaling](https://reactome.org/content/detail/R-HSA-2173788) | electronic |
| [NPAS4 regulates expression of target genes](https://reactome.org/content/detail/R-HSA-9768919) | electronic |

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

**Molecular function:** nuclear export signal receptor activity.

**Biological process:** ribosomal subunit export from nucleus, ribosomal large subunit export from nucleus, ribosomal small subunit export from nucleus, protein export from nucleus, nucleocytoplasmic transport, regulation of proteasomal ubiquitin-dependent protein catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-19.

**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 | 2024-01-19 |

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

## Similar variants {#similar}

Related EMB variant pages (same residue, condition, or type): [XPO1 c.888+9A>G](/variant/xpo1-c-888-plus-9a-g), [XPO1 p.Arg305=](/variant/xpo1-p-arg305), [XPO1 p.Leu625=](/variant/xpo1-p-leu625), [XPO1 p.Lys757=](/variant/xpo1-p-lys757), [XPO1 p.Thr846=](/variant/xpo1-p-thr846), [XPO1 c.1887+1G>T](/variant/xpo1-c-1887-plus-1g-t), [XPO1 c.888+1G>A](/variant/xpo1-c-888-plus-1g-a), [XPO1 p.Arg765Ter](/variant/xpo1-p-arg765ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3088540). 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.*