# NM_001972.4(ELANE):c.659G>C (p.Arg220Pro)

https://sugi.bio/variant/elane-p-arg220pro

## Summary

**ELANE p.Arg220Pro (c.659G>C)** is classified **Conflicting classifications of pathogenicity** in ELANE (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2019-10-29). AlphaMissense: ambiguous (0.5591); Very rare (popmax 0.000678%, nfe); Associated with cyclic neutropenia.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs137854445 · 2 submitters · 2 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.000678%, nfe)

## For patients & families {#patients}

This is a change in the ELANE gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to cyclic neutropenia.

*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 |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Diagnostic panels | ELANE is a diagnostic-grade gene on 8 Genomics England panels |

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

- Sinusitis — Very frequent (99-80%)
- Headache — Very frequent (99-80%)
- Bone pain — Very frequent (99-80%)
- Cyclic neutropenia — Very frequent (99-80%)
- Oral ulcer — Frequent (79-30%)
- Gingivitis — Frequent (79-30%)
- Recurrent skin infections — Frequent (79-30%)
- Recurrent fever — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006229/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ELANE](https://sugi.bio/atlas/gene/ELANE/) |
| Protein change (HGVS p.) | p.Arg220Pro |
| Coding change (HGVS c.) | c.659G>C |
| MANE Select transcript | [NM_001972](https://www.ncbi.nlm.nih.gov/nuccore/NM_001972) |
| dbSNP | [rs137854445](https://www.ncbi.nlm.nih.gov/snp/rs137854445/) |
| Variant type | single nucleotide variant |
| Location | chr19:856019-856019 (GRCh38) |
| ClinVar | [VCV851966](https://www.ncbi.nlm.nih.gov/clinvar/variation/851966/) |

**All HGVS expressions:** `LRG_46:g.1355G>C`, `LRG_57:g.8729G>C`, `LRG_57t1:c.659G>C`, `NC_000019.10:g.856019G>C`, `NC_000019.9:g.856019G>C`, `NG_007274.1:g.1355G>C`, `NG_009627.1:g.8729G>C`, `NM_001972.4:c.659G>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.5591) — no call either way
- REVEL 0.607 (indeterminate)
- SaProt LLR -8.514 (tolerated)
- Conservation: phyloP 4.722, GERP -0.162, phastCons 1 — highly conserved
- CADD: **PHRED 18.63**. 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 1.04** across the covering region of the MANE Select transcript (852,990–856,161), spanning 3,171 bp. Chi-square p 0.52. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, G>A, IS in the release and scores Δ0.50 acceptor gain, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.000678%** (nfe) · FAF95 0.000292% · FAF99 0.000211% · 8/1,180,036 in the highest group · 8/1,613,402 alleles overall — very rare (popmax 0.000678%, nfe).

*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}

**ELANE** population constraint: LOEUF 1.245, pLI 0.00041675, missense-Z -0.55026. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **neutropenia** — Definitive (AD)

## Protein context {#protein}

Residue **220** lies in a UniProt-annotated variant site (in ch and scn1; loss of interaction with notch2nl and loss of notch2nl and notch2 proteolytic cleavage); a β-strand; the peptidase s1 domain.

AlphaFold model confidence (whole protein): pLDDT 88.42, 76% of residues very-high.

**38 experimental structure(s)** (PDB): [1B0F](https://www.rcsb.org/structure/1B0F), [1H1B](https://www.rcsb.org/structure/1H1B), [1HNE](https://www.rcsb.org/structure/1HNE), [1PPF](https://www.rcsb.org/structure/1PPF), [1PPG](https://www.rcsb.org/structure/1PPG), [2RG3](https://www.rcsb.org/structure/2RG3).

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

*Describes the biological roles of ELANE (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:** ELANE's established molecular role includes protease binding. p.Arg220Pro falls in the peptidase s1 domain.


### Pathways affected {#pathways}

ELANE participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of Matrix Metalloproteinases](https://reactome.org/content/detail/R-HSA-1592389) | curated |
| [Antimicrobial peptides](https://reactome.org/content/detail/R-HSA-6803157) | curated |
| [Expression of NOTCH2NL genes](https://reactome.org/content/detail/R-HSA-9911233) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Pyroptosis](https://reactome.org/content/detail/R-HSA-5620971) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | electronic |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | electronic |

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

**Molecular function:** protease binding, transcription corepressor activity, endopeptidase activity, serine-type endopeptidase activity, heparin binding, peptidase activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, biosynthetic process of antibacterial peptides active against Gram-negative bacteria, proteolysis, response to UV, negative regulation of heterochromatin formation, negative regulation of chemokine production.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2019-10-29.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 2 submissions (2017–2019); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-10-29 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-11-14 |

## Associated conditions {#conditions}

[cyclic neutropenia](https://sugi.bio/atlas/disease/cyclic-neutropenia/), [neutropenia, severe congenital, 1, autosomal dominant](https://sugi.bio/atlas/disease/neutropenia-severe-congenital-1-autosomal-dominant/).

**Reported phenotype names (ClinVar):** Cyclical neutropenia, Neutropenia, severe congenital, 1, autosomal dominant, ELANE-related disorders, Cyclic hematopoiesis, Cyclic Neutropenia.

## Same-residue context {#hotspot}

Residue **220** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [ELANE p.Arg220Gln](/variant/elane-p-arg220gln), [ELANE p.Arg220Trp](/variant/elane-p-arg220trp). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ELANE variant pages (same residue, condition, or type): [ELANE p.Arg220Gln](/variant/elane-p-arg220gln), [ELANE p.Arg220Trp](/variant/elane-p-arg220trp), [ELANE p.Arg220Gly](/variant/elane-p-arg220gly), [ELANE c.597+1G>A](/variant/elane-c-597-plus-1g-a), [ELANE c.597+1G>C](/variant/elane-c-597-plus-1g-c), [ELANE c.597+1G>T](/variant/elane-c-597-plus-1g-t), [ELANE c.597+5G>A](/variant/elane-c-597-plus-5g-a), [ELANE p.Ala57Thr](/variant/elane-p-ala57thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 851966). 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.*