# NM_004826.4(ECEL1):c.110_155del (p.Phe37fs)

https://sugi.bio/variant/ecel1-p-phe37fs

## Summary

**ECEL1 p.Phe37fs (c.110_155del)** is classified **Pathogenic** in ECEL1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-06-01). Ultra-rare (popmax 0.0551%, amr); Associated with Inborn genetic diseases.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1341894581 · 10 submitters · 2 linked conditions · ultra-rare (popmax 0.0551%, amr)

## For patients & families {#patients}

This is a change in the ECEL1 gene that is considered disease-causing, submitted by 10 submitters, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [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.Phe37fs |
| Coding change (HGVS c.) | c.110_155del |
| MANE Select transcript | [NM_004826](https://www.ncbi.nlm.nih.gov/nuccore/NM_004826) |
| dbSNP | [rs1341894581](https://www.ncbi.nlm.nih.gov/snp/rs1341894581/) |
| Variant type | Deletion |
| Location | chr2:232486499-232486544 (GRCh38) |
| ClinVar | [VCV435024](https://www.ncbi.nlm.nih.gov/clinvar/variation/435024/) |

**All HGVS expressions:** `NC_000002.11:g.233351216_233351261del`, `NC_000002.12:g.232486506_232486551del`, `NG_034065.1:g.6316_6361del`, `NM_001290787.2:c.110_155del`, `NM_004826.3:c.110_155del`, `NM_004826.4:c.110_155del`

## 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 0.398, GERP -1.58, phastCons 0.995 — weakly conserved position
- 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 2 of 18**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 33.0**. 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** — 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 (gnomAD v4.1): grpmax **0.0551%** (amr) · FAF95 0.0339% · FAF99 0.0274% · 15/27,218 in the highest group · 79/1,383,780 alleles overall — ultra-rare (popmax 0.0551%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0551% | 1,815 |
| African / African-American | 0.00612% | 16,335 |
| Remaining individuals (not grpmax-eligible) | 0.00569% | 17,568 |
| European (non-Finnish) | 0.0051% | 19,619 |
| East Asian | 0.00309% | 32,396 |
| South Asian | 0.00167% | 59,904 |

*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}


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

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-01.

**Submitter consensus:** unanimous (10/10 Pathogenic).

**Submission history:** 10 submissions (2016–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Pathogenic | criteria provided, single submitter | clinical testing | 2016-05-05 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-17 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-15 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-25 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-06-03 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-19 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2017-01-17 |
| Genomic Medicine Lab, University of California San Francisco | Pathogenic | criteria provided, single submitter | clinical testing | 2019-08-15 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2026-06-01 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-04 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [distal arthrogryposis type 5D](https://sugi.bio/atlas/disease/distal-arthrogryposis-type-5d/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Distal arthrogryposis type 5D, not provided, ECEL1-related disorders, none provided.

## Similar variants {#similar}

Related ECEL1 variant pages (same residue, condition, or type): [ECEL1 p.Phe37Cys](/variant/ecel1-p-phe37cys), [ECEL1 p.Gly170fs](/variant/ecel1-p-gly170fs), [ECEL1 p.Gly27fs](/variant/ecel1-p-gly27fs), [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 435024). 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.*