# NM_198449.3(EMB):c.526A>T (p.Thr176Ser)

https://sugi.bio/variant/emb-p-thr176ser

## Summary

**EMB p.Thr176Ser (c.526A>T)** is classified **Uncertain significance** in EMB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: likely benign (0.152); Very rare (popmax 0.0017%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.0017%, amr)

## 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.Thr176Ser |
| Coding change (HGVS c.) | c.526A>T |
| MANE Select transcript | [NM_003400](https://www.ncbi.nlm.nih.gov/nuccore/NM_003400) (variant reported on NM_198449) |
| Variant type | single nucleotide variant |
| Location | chr5:50405799-50405799 (GRCh38) |
| ClinVar | [VCV4017707](https://www.ncbi.nlm.nih.gov/clinvar/variation/4017707/) |

**All HGVS expressions:** `NC_000005.10:g.50405799T>A`, `NC_000005.9:g.49701633T>A`, `NM_198449.3:c.526A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.152)
- REVEL 0.062 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.835 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.442, GERP -0.84 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 16.52**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0017%** (amr) · 1/58,672 in the highest group · 1/1,453,244 alleles overall — very rare (popmax 0.0017%, amr).

*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 **176** lies in the 'necessary for htlv-1 rex-mediated mrna export' region; an α-helix.

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.Thr176Ser 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 2025-04-17.

**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 | 2025-04-17 |

**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 4017707). 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.*