# NM_004826.4(ECEL1):c.1252C>A (p.Arg418Ser)

https://sugi.bio/variant/ecel1-p-arg418ser

## Summary

**ECEL1 p.Arg418Ser (c.1252C>A)** is classified **Pathogenic** in ECEL1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2013-01-10). AlphaMissense: likely pathogenic (0.9552); Absent from gnomAD v4.1; Associated with distal arthrogryposis type 5D.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs587776919 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## 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.Arg418Ser |
| Coding change (HGVS c.) | c.1252C>A |
| MANE Select transcript | [NM_004826](https://www.ncbi.nlm.nih.gov/nuccore/NM_004826) |
| dbSNP | [rs587776919](https://www.ncbi.nlm.nih.gov/snp/rs587776919/) |
| Variant type | single nucleotide variant |
| Location | chr2:232484156-232484156 (GRCh38) |
| ClinVar | [VCV39490](https://www.ncbi.nlm.nih.gov/clinvar/variation/39490/) |

**All HGVS expressions:** `NC_000002.11:g.233348866G>T`, `NC_000002.12:g.232484156G>T`, `NG_034065.1:g.8704C>A`, `NM_001290787.2:c.1252C>A`, `NM_004826.4:c.1252C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9552) — concordant with the pathogenic call
- REVEL 0.802 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -9.867 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- SpliceAI predicts **acceptor gain** (Δ 0.49) — consistent with the pathogenic call
- Conservation: phyloP 5.036, GERP 1.64, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. 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.*
- Regional missense constraint: **o/e 0.96** across the covering region of the MANE Select transcript (232,480,156–232,486,653), spanning 6,497 bp. Chi-square p 0.15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.05**, donor loss **0.00**, acceptor gain **0.49**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.49**, 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}

**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 **418** lies in a UniProt-annotated variant site (in da5d); the peptidase m13 domain.

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

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2013-01-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2013-01-10 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **418** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [ECEL1 p.Arg418His](/variant/ecel1-p-arg418his), [ECEL1 p.Arg418Cys](/variant/ecel1-p-arg418cys). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ECEL1 variant pages (same residue, condition, or type): [ECEL1 p.Arg418Cys](/variant/ecel1-p-arg418cys), [ECEL1 p.Arg418His](/variant/ecel1-p-arg418his), [ECEL1 c.1685+1G>A](/variant/ecel1-c-1685-plus-1g-a), [ECEL1 c.2151+2T>C](/variant/ecel1-c-2151-plus-2t-c), [ECEL1 c.966+1G>A](/variant/ecel1-c-966-plus-1g-a), [ECEL1 p.Ala675Thr](/variant/ecel1-p-ala675thr), [ECEL1 p.Arg333Ter](/variant/ecel1-p-arg333ter), [ECEL1 p.Arg395Gln](/variant/ecel1-p-arg395gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 39490). 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.*