# NM_004826.4(ECEL1):c.1672del (p.Val558fs)

https://sugi.bio/variant/ecel1-p-val558fs

## Summary

**ECEL1 p.Val558fs (c.1672del)** is classified **Pathogenic** in ECEL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-16). No gnomAD frequency available for this variant; Associated with distal arthrogryposis type 5D.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2469642191 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ECEL1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to distal arthrogryposis type 5D.

*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 recessive |
| Age of onset (of this condition) | Neonatal |
| Diagnostic panels | ECEL1 is a diagnostic-grade gene on 6 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013059/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ECEL1](https://sugi.bio/atlas/gene/ECEL1/) |
| Protein change (HGVS p.) | p.Val558fs |
| Coding change (HGVS c.) | c.1672del |
| MANE Select transcript | [NM_004826](https://www.ncbi.nlm.nih.gov/nuccore/NM_004826) |
| dbSNP | [rs2469642191](https://www.ncbi.nlm.nih.gov/snp/rs2469642191/) |
| Variant type | Deletion |
| Location | chr2:232482864-232482864 (GRCh38) |
| ClinVar | [VCV1706601](https://www.ncbi.nlm.nih.gov/clinvar/variation/1706601/) |

**All HGVS expressions:** `NC_000002.11:g.233347575del`, `NC_000002.12:g.232482865del`, `NG_034065.1:g.9996del`, `NM_001290787.2:c.1672del`, `NM_004826.4:c.1672del`

## Computational & population evidence {#evidence}

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

- **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 9.194, GERP 5.47, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.099, pLI 1.7007e-27. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 18**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ECEL1** population constraint: LOEUF 1.099, pLI 1.7007e-27, missense-Z -0.41176. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **558** lies in a disulfide bond; the peptidase m13 domain.

AlphaFold model confidence (whole protein): pLDDT 88.62, 77% of residues very-high.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-16.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-16 |

## Associated conditions {#conditions}

[distal arthrogryposis type 5D](https://sugi.bio/atlas/disease/distal-arthrogryposis-type-5d/).

**Reported phenotype names (ClinVar):** Distal arthrogryposis type 5D.

## Similar variants {#similar}

Related ECEL1 variant pages (same residue, condition, or type): [ECEL1 p.Gly170fs](/variant/ecel1-p-gly170fs), [ECEL1 p.Gly27fs](/variant/ecel1-p-gly27fs), [ECEL1 p.Phe37fs](/variant/ecel1-p-phe37fs), [ECEL1 p.Arg49_Ser50delinsPro](/variant/ecel1-p-arg49-ser50delinspro), [ECEL1 p.Gln348fs](/variant/ecel1-p-gln348fs), [ECEL1 p.Glu13fs](/variant/ecel1-p-glu13fs), [ECEL1 p.Gly133fs](/variant/ecel1-p-gly133fs), [ECEL1 p.Pro595_Asp596del](/variant/ecel1-p-pro595-asp596del).

### 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 1706601). 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.*