# NM_004826.4(ECEL1):c.1779C>T (p.Tyr593=)

https://sugi.bio/variant/ecel1-p-tyr593

## Summary

**ECEL1 p.Tyr593= (c.1779C>T)** is classified **Likely benign** in ECEL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-06). Ultra-rare (popmax 0.0132%, sas).

**At a glance:** Likely benign · review: Single submitter · rsID rs552489480 · 1 submitter · ultra-rare (popmax 0.0132%, sas)

## For patients & families {#patients}

This is a change in the ECEL1 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 | [ECEL1](https://sugi.bio/atlas/gene/ECEL1/) |
| Protein change (HGVS p.) | p.Tyr593= |
| Coding change (HGVS c.) | c.1779C>T |
| MANE Select transcript | [NM_004826](https://www.ncbi.nlm.nih.gov/nuccore/NM_004826) |
| dbSNP | [rs552489480](https://www.ncbi.nlm.nih.gov/snp/rs552489480/) |
| Variant type | single nucleotide variant |
| Location | chr2:232482435-232482435 (GRCh38) |
| ClinVar | [VCV738817](https://www.ncbi.nlm.nih.gov/clinvar/variation/738817/) |

**All HGVS expressions:** `NC_000002.11:g.233347145G>A`, `NC_000002.12:g.232482435G>A`, `NG_034065.1:g.10425C>T`, `NM_001290787.2:c.1773C>T`, `NM_004826.4:c.1779C>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 -1.903, GERP -7.06 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.305**. 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, Δ0.30 acceptor loss), 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.*
- Pangolin: Δ**0.24** (loss), gain 0.00 / loss 0.24. SpliceAI below 0.2. 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 **0.0132%** (sas) · FAF95 0.00751% · FAF99 0.00593% · 12/91,084 in the highest group · 70/1,613,990 alleles overall — ultra-rare (popmax 0.0132%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0132% | 7,590 |
| Admixed American | 0.00666% | 15,007 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,837 |
| East Asian | 0.00446% | 22,436 |
| European (non-Finnish) | 0.00415% | 24,082 |

*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 **593** 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-04-06.

**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 | 2018-04-06 |

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

## Same-residue context {#hotspot}

Residue **593** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ECEL1 p.Tyr593Ter](/variant/ecel1-p-tyr593ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ECEL1 variant pages (same residue, condition, or type): [ECEL1 p.Tyr593Ter](/variant/ecel1-p-tyr593ter), [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 738817). 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.*