# NM_001972.4(ELANE):c.654C>T (p.Phe218=)

https://sugi.bio/variant/elane-p-phe218

## Summary

**ELANE p.Phe218= (c.654C>T)** is classified **Benign/Likely benign** in ELANE (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Low-frequency (popmax 1.27%, eas); Associated with cyclic neutropenia.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs148492780 · 7 submitters · 3 linked conditions · low-frequency (popmax 1.27%, eas)

## For patients & families {#patients}

This is a change in the ELANE gene that is classified as benign/likely benign — not considered disease-causing, submitted by 7 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.Phe218= |
| Coding change (HGVS c.) | c.654C>T |
| MANE Select transcript | [NM_001972](https://www.ncbi.nlm.nih.gov/nuccore/NM_001972) |
| dbSNP | [rs148492780](https://www.ncbi.nlm.nih.gov/snp/rs148492780/) |
| Variant type | single nucleotide variant |
| Location | chr19:856014-856014 (GRCh38) |
| ClinVar | [VCV258499](https://www.ncbi.nlm.nih.gov/clinvar/variation/258499/) |

**All HGVS expressions:** `LRG_46:g.1350C>T`, `LRG_57:g.8724C>T`, `LRG_57t1:c.654C>T`, `NC_000019.10:g.856014C>T`, `NC_000019.9:g.856014C>T`, `NG_007274.1:g.1350C>T`, `NG_009627.1:g.8724C>T`, `NM_001972.4:c.654C>T`

## 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 -0.202, GERP -1.44, phastCons 0.016 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.765**. 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 **1.27%** (eas) · FAF95 1.18% · FAF99 1.15% · 570/44,884 in the highest group · 875/1,613,562 alleles overall — low-frequency (popmax 1.27%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 1.27% | 79 |
| Finnish (not grpmax-eligible) | 0.223% | 449 |
| Remaining individuals (not grpmax-eligible) | 0.0384% | 2,604 |
| European (non-Finnish) | 0.0109% | 9,148 |
| African / African-American | 0.00932% | 10,725 |
| Admixed American | 0.00333% | 30,017 |
| South Asian | 0.0022% | 45,545 |

*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 **218** lies in a β-strand; a disulfide bond; 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.Phe218= 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (5 Likely benign, 2 Benign).

**Submission history:** 7 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing |  |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-22 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-01 |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Likely benign | criteria provided, single submitter | clinical testing | 2021-08-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-28 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cyclical neutropenia, not specified, not provided, Neutropenia, severe congenital, 1, autosomal dominant, Autoinflammatory syndrome, Inborn genetic diseases, Cyclic Neutropenia, Cyclic hematopoiesis, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related ELANE variant pages (same residue, condition, or type): [ELANE p.Phe218Leu](/variant/elane-p-phe218leu), [ELANE p.Phe218Ser](/variant/elane-p-phe218ser), [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), [ELANE p.Ala61Val](/variant/elane-p-ala61val).

### 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 258499). 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.*