# NM_000121.4(EPOR):c.1320A>G (p.Thr440=)

https://sugi.bio/variant/epor-p-thr440

## Summary

**EPOR p.Thr440= (c.1320A>G)** is classified **Likely benign** in EPOR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-30). Absent from gnomAD v4.1; Associated with primary familial polycythemia due to EPO receptor mutation.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the EPOR gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to primary familial polycythemia due to EPO receptor mutation.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | All ages |
| Diagnostic panels | EPOR is a diagnostic-grade gene on 1 Genomics England panel |

**Commonly reported features of Primary familial polycythemia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Epistaxis — Very frequent (99-80%)
- Polycythemia — Very frequent (99-80%)
- Dyspnea — Very frequent (99-80%)
- Headache — Very frequent (99-80%)
- Vertigo — Very frequent (99-80%)
- Venous thrombosis — Very frequent (99-80%)
- Abnormal hemoglobin — Very frequent (99-80%)
- Fatigue — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009843/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EPOR](https://sugi.bio/atlas/gene/EPOR/) |
| Protein change (HGVS p.) | p.Thr440= |
| Coding change (HGVS c.) | c.1320A>G |
| MANE Select transcript | [NM_000121](https://www.ncbi.nlm.nih.gov/nuccore/NM_000121) |
| Variant type | single nucleotide variant |
| Location | chr19:11378191-11378191 (GRCh38) |
| ClinVar | [VCV4686000](https://www.ncbi.nlm.nih.gov/clinvar/variation/4686000/) |

**All HGVS expressions:** `NC_000019.10:g.11378191T>C`, `NC_000019.9:g.11488867T>C`, `NG_021395.1:g.11152A>G`, `NM_000121.4:c.1320A>G`, `NR_033663.2:n.1677A>G`

## 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 -4.945, GERP -3.69 — fast-evolving / accelerated position
- CADD: **PHRED 0.405**. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**EPOR** population constraint: LOEUF 0.787, pLI 0.00041923, missense-Z 1.0613. *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 67.74, 36% of residues very-high.

**22 experimental structure(s)** (PDB): [1CN4](https://www.rcsb.org/structure/1CN4), [1EBA](https://www.rcsb.org/structure/1EBA), [1EBP](https://www.rcsb.org/structure/1EBP), [1EER](https://www.rcsb.org/structure/1EER), [1ERN](https://www.rcsb.org/structure/1ERN), [2JIX](https://www.rcsb.org/structure/2JIX).

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

*Describes the biological roles of EPOR (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:** EPOR's established molecular role includes erythropoietin receptor activity.


### Pathways affected {#pathways}

EPOR participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Erythropoietin activates Phosphoinositide-3-kinase (PI3K)](https://reactome.org/content/detail/R-HSA-9027276) | electronic |
| [Erythropoietin activates Phospholipase C gamma (PLCG)](https://reactome.org/content/detail/R-HSA-9027277) | electronic |
| [Erythropoietin activates RAS](https://reactome.org/content/detail/R-HSA-9027284) | electronic |
| [Erythropoietin activates STAT5](https://reactome.org/content/detail/R-HSA-9027283) | electronic |
| [Signaling by Erythropoietin](https://reactome.org/content/detail/R-HSA-9006335) | electronic |

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

**Molecular function:** erythropoietin receptor activity, identical protein binding.

**Biological process:** erythropoietin-mediated signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-30.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely Benign | criteria provided, single submitter | clinical testing | 2025-07-30 |

## Associated conditions {#conditions}

[primary familial polycythemia due to EPO receptor mutation](https://sugi.bio/atlas/disease/primary-familial-polycythemia-due-to-epo-receptor-mutation/).

**Reported phenotype names (ClinVar):** Primary familial polycythemia due to EPO receptor mutation, POLYCYTHEMIA, PRIMARY FAMILIAL AND CONGENITAL, Primary Familial Congenital Polycythemia, Erythrocytosis, familial, 1, ERYTHROCYTOSIS, SOMATIC.

## Similar variants {#similar}

Related EPOR variant pages (same residue, condition, or type): [EPOR p.Trp439Ter](/variant/epor-p-trp439ter), [EPOR p.Pro327Leu](/variant/epor-p-pro327leu), [EPOR c.115+7A>G](/variant/epor-c-115-plus-7a-g), [EPOR c.-55G>A](/variant/epor-c-minus-55g-a), [EPOR c.*35G>A](/variant/epor-c-star-35g-a), [EPOR p.Ala186=](/variant/epor-p-ala186), [EPOR p.Ala219=](/variant/epor-p-ala219), [EPOR p.Arg56=](/variant/epor-p-arg56).

### 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 4686000). 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.*