# NM_004826.4(ECEL1):c.1810G>A (p.Gly604Arg)

https://sugi.bio/variant/ecel1-p-gly604arg

## Summary

**ECEL1 p.Gly604Arg (c.1810G>A)** is classified **Conflicting classifications of pathogenicity** in ECEL1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.9956); Very rare (popmax 0.00668%, eas); Associated with distal arthrogryposis type 5D.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs745378093 · 3 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00668%, eas)

## 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 3 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.Gly604Arg |
| Coding change (HGVS c.) | c.1810G>A |
| MANE Select transcript | [NM_004826](https://www.ncbi.nlm.nih.gov/nuccore/NM_004826) |
| dbSNP | [rs745378093](https://www.ncbi.nlm.nih.gov/snp/rs745378093/) |
| Variant type | single nucleotide variant |
| Location | chr2:232481836-232481836 (GRCh38) |
| ClinVar | [VCV1705569](https://www.ncbi.nlm.nih.gov/clinvar/variation/1705569/) |

**All HGVS expressions:** `NC_000002.11:g.233346546C>T`, `NC_000002.12:g.232481836C>T`, `NG_034065.1:g.11024G>A`, `NM_001290787.2:c.1804G>A`, `NM_004826.2:c.1810G>A`, `NM_004826.4:c.1810G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9956)
- REVEL 0.955 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.959 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor gain** (Δ 0.69) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 7.618, GERP 6.21, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in ECEL1 (of 4,570 modeled).
- CADD: **PHRED 36.0**. 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 **0.01**, donor loss **0.00**, acceptor gain **0.69**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.69**, donor gain **0.00**.
- Pangolin: Δ**0.42** (gain), gain 0.42 / loss 0.09. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00668%** (eas) · FAF95 0.00177% · FAF99 0.000891% · 3/44,878 in the highest group · 9/1,461,626 alleles overall — very rare (popmax 0.00668%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00668% | 14,959 |
| South Asian | 0.0022% | 45,544 |
| Admixed American | 0.00167% | 60,024 |
| European (non-Finnish) | 0.000254% | 393,337 |

*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 **604** 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 2026-01-26.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 3 submissions (2022–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-01 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-13 |
| Medical and Scientific Branch, Hong Kong Genome Institute | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-01-26 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Distal arthrogryposis type 5D, not provided, none provided.

## Similar variants {#similar}

Related ECEL1 variant pages (same residue, condition, or type): [ECEL1 p.Gly604Trp](/variant/ecel1-p-gly604trp), [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).

### 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 1705569). 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.*