# NM_001972.4(ELANE):c.136T>C (p.Ser46Pro)

https://sugi.bio/variant/elane-p-ser46pro

## Summary

**ELANE p.Ser46Pro (c.136T>C)** is classified **Pathogenic** in ELANE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.9838); Absent from gnomAD v4.1; Associated with neutropenia, severe congenital, 1, autosomal dominant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2035616857 · 1 submitter · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ELANE gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to neutropenia, severe congenital, 1, autosomal dominant.

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

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

- Decreased total neutrophil count — Obligate (100%)
- Recurrent bacterial infections — Very frequent (99-80%)
- Recurrent viral infections — Very frequent (99-80%)
- Oral ulcer — Frequent (79-30%)
- Gingivitis — Frequent (79-30%)
- Periodontitis — Frequent (79-30%)
- Recurrent skin infections — Frequent (79-30%)
- Lymphopenia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025849/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.Ser46Pro |
| Coding change (HGVS c.) | c.136T>C |
| MANE Select transcript | [NM_001972](https://www.ncbi.nlm.nih.gov/nuccore/NM_001972) |
| dbSNP | [rs2035616857](https://www.ncbi.nlm.nih.gov/snp/rs2035616857/) |
| Variant type | single nucleotide variant |
| Location | chr19:852944-852944 (GRCh38) |
| ClinVar | [VCV952580](https://www.ncbi.nlm.nih.gov/clinvar/variation/952580/) |

**All HGVS expressions:** `LRG_57:g.5654T>C`, `LRG_57t1:c.136T>C`, `NC_000019.10:g.852944T>C`, `NC_000019.9:g.852944T>C`, `NG_009627.1:g.5654T>C`, `NM_001972.4:c.136T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9838) — concordant with the pathogenic call
- REVEL 0.816 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.682 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor loss** (Δ 0.30) — consistent with the pathogenic call
- Conservation: phyloP 5.707, GERP 1.44, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in ELANE (of 1,557 modeled).
- CADD: **PHRED 26.3**. 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 0.31** across the covering region of the MANE Select transcript (852,927–852,989), spanning 62 bp — the region is depleted of missense variation. Chi-square p 0.00023. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.30**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.30**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- 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}

**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 **46** lies in a β-strand; a UniProt-annotated variant site (in scn1); a UniProt-annotated variant site (in ch and scn1); 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.Ser46Pro 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-21.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-21 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **46** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [ELANE p.Ser46Tyr](/variant/elane-p-ser46tyr), [ELANE p.Ser46Phe](/variant/elane-p-ser46phe), [ELANE p.Ser46_Leu47del](/variant/elane-p-ser46-leu47del). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ELANE variant pages (same residue, condition, or type): [ELANE p.Ser46Phe](/variant/elane-p-ser46phe), [ELANE p.Ser46=](/variant/elane-p-ser46), [ELANE p.Ser46Tyr](/variant/elane-p-ser46tyr), [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 2026-10-11); 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 952580). 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.*