# NM_001397.3(ECE1):c.729C>T (p.Ala243=)

https://sugi.bio/variant/ece1-p-ala243

## Summary

**ECE1 p.Ala243= (c.729C>T)** is classified **Likely benign** in ECE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-02). Ultra-rare (popmax 0.0154%, sas).

**At a glance:** Likely benign · review: Single submitter · rsID rs763305486 · 1 submitter · ultra-rare (popmax 0.0154%, sas)

## For patients & families {#patients}

This is a change in the ECE1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [ECE1](https://sugi.bio/atlas/gene/ECE1/) |
| Protein change (HGVS p.) | p.Ala243= |
| Coding change (HGVS c.) | c.729C>T |
| MANE Select transcript | [NM_001397](https://www.ncbi.nlm.nih.gov/nuccore/NM_001397) |
| dbSNP | [rs763305486](https://www.ncbi.nlm.nih.gov/snp/rs763305486/) |
| Variant type | single nucleotide variant |
| Location | chr1:21258726-21258726 (GRCh38) |
| ClinVar | [VCV735770](https://www.ncbi.nlm.nih.gov/clinvar/variation/735770/) |

**All HGVS expressions:** `NC_000001.10:g.21585219G>A`, `NC_000001.11:g.21258726G>A`, `NG_013008.2:g.91816C>T`, `NM_001113347.2:c.693C>T`, `NM_001113348.2:c.681C>T`, `NM_001113349.2:c.720C>T`, `NM_001397.3:c.729C>T`

## 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 -8.437, GERP -3.81 — fast-evolving / accelerated position
- CADD: **PHRED 5.303**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.35 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0154%** (sas) · FAF95 0.00919% · FAF99 0.00735% · 14/91,084 in the highest group · 73/1,614,034 alleles overall — ultra-rare (popmax 0.0154%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0154% | 6,506 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,414 |
| European (non-Finnish) | 0.00432% | 23,138 |
| East Asian | 0.00223% | 44,896 |
| Admixed American | 0.00167% | 60,000 |

*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}

**ECE1** population constraint: LOEUF 0.482, pLI 0.98765, missense-Z 2.4896. *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 **243** lies in a disulfide bond; the peptidase m13 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 91.16, 85% of residues very-high.

**1 experimental structure(s)** (PDB): [3DWB](https://www.rcsb.org/structure/3DWB).

## What this gene does {#gene-function}

*Describes the biological roles of ECE1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ECE1's established molecular role includes endopeptidase activity. p.Ala243= falls in the peptidase m13 domain.


### Pathways affected {#pathways}

ECE1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Peptide ligand-binding receptors](https://reactome.org/content/detail/R-HSA-375276) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** endopeptidase activity, zinc ion binding, protein homodimerization activity.

**Biological process:** positive regulation of receptor recycling, heart development, substance P catabolic process, bradykinin catabolic process, calcitonin catabolic process, protein processing.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-03-02.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2018-03-02 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related ECE1 variant pages (same residue, condition, or type): [ECE1 p.Thr312Met](/variant/ece1-p-thr312met), [ECE1 c.1020+15G>A](/variant/ece1-c-1020-plus-15g-a), [ECE1 c.1164-5C>T](/variant/ece1-c-1164-minus-5c-t), [ECE1 c.1278+7C>T](/variant/ece1-c-1278-plus-7c-t), [ECE1 c.1782-4C>A](/variant/ece1-c-1782-minus-4c-a), [ECE1 c.828+8T>C](/variant/ece1-c-828-plus-8t-c), [ECE1 p.Asn397Ser](/variant/ece1-p-asn397ser), [ECE1 p.Asp547=](/variant/ece1-p-asp547).

### 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 735770). 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.*