# NM_004826.4(ECEL1):c.494T>C (p.Leu165Pro)

https://sugi.bio/variant/ecel1-p-leu165pro

## Summary

**ECEL1 p.Leu165Pro (c.494T>C)** is classified **Conflicting classifications of pathogenicity** in ECEL1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-02-28). AlphaMissense: likely pathogenic (0.9599); Ultra-rare (popmax 0.0178%, mid); Associated with distal arthrogryposis type 5D.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs765305996 · 7 submitters · 2 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0178%, mid)

## For patients & families {#patients}

This is a change in the ECEL1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, 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.Leu165Pro |
| Coding change (HGVS c.) | c.494T>C |
| MANE Select transcript | [NM_004826](https://www.ncbi.nlm.nih.gov/nuccore/NM_004826) |
| dbSNP | [rs765305996](https://www.ncbi.nlm.nih.gov/snp/rs765305996/) |
| Variant type | single nucleotide variant |
| Location | chr2:232486160-232486160 (GRCh38) |
| ClinVar | [VCV521056](https://www.ncbi.nlm.nih.gov/clinvar/variation/521056/) |

**All HGVS expressions:** `NC_000002.11:g.233350870A>G`, `NC_000002.12:g.232486160A>G`, `NG_034065.1:g.6700T>C`, `NM_001290787.2:c.494T>C`, `NM_004826.3:c.494T>C`, `NM_004826.4:c.494T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9599)
- REVEL 0.842 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -17.082 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 10.864, GERP 0.525, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.3**. 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 0.96** 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: **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 **0.0178%** (mid) · FAF95 0.0088% · FAF99 0.00699% · 1/5,606 in the highest group · 14/1,422,786 alleles overall — ultra-rare (popmax 0.0178%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0178% | 5,606 |
| South Asian | 0.0149% | 6,706 |

*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 **165** 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-02-28.

**Submitter consensus:** conflicting (3 Uncertain significance, 3 Likely pathogenic, 1 Pathogenic).

**Submission history:** 7 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Rare Disease Group, Clinical Genetics, Karolinska Institutet | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-04-09 |
| CENTOGENE GmbH and LLC - Guiding Precision Medicine | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-02-27 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-11-16 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-10 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-08-06 |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-02-28 |
| Institute of Human Genetics Munich, TUM University Hospital | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-15 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Distal arthrogryposis type 5D, Inborn genetic diseases, Arthrogryposis multiplex congenita, not provided, none provided, Guérin-Stern syndrome, Congenital multiple arthrogryposis, Fibrous ankylosis of multiple joints, Congenital arthromyodysplasia, Myodystrophia fetalis deformans.

## Similar variants {#similar}

Related ECEL1 variant pages (same residue, condition, or type): [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), [ECEL1 p.Arg418Cys](/variant/ecel1-p-arg418cys), [ECEL1 p.Gln435Ter](/variant/ecel1-p-gln435ter).

### 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 521056). 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.*