# NM_004826.4(ECEL1):c.1656G>A (p.Lys552=)

https://sugi.bio/variant/ecel1-p-lys552

## Summary

**ECEL1 p.Lys552= (c.1656G>A)** is classified **Benign/Likely benign** in ECEL1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2024-11-26). Rare (popmax 0.735%, nfe).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs1190429 · 9 submitters · rare (popmax 0.735%, nfe)

## For patients & families {#patients}

This is a change in the ECEL1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 9 submitters.

*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.Lys552= |
| Coding change (HGVS c.) | c.1656G>A |
| MANE Select transcript | [NM_004826](https://www.ncbi.nlm.nih.gov/nuccore/NM_004826) |
| dbSNP | [rs1190429](https://www.ncbi.nlm.nih.gov/snp/rs1190429/) |
| Variant type | single nucleotide variant |
| Location | chr2:232482880-232482880 (GRCh38) |
| ClinVar | [VCV210908](https://www.ncbi.nlm.nih.gov/clinvar/variation/210908/) |

**All HGVS expressions:** `NC_000002.11:g.233347590C>T`, `NC_000002.12:g.232482880C>T`, `NG_034065.1:g.9980G>A`, `NM_001290787.2:c.1656G>A`, `NM_004826.4:c.1656G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.57) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 3.974, GERP 5.47, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.48**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.57**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss, 6 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.735%** (nfe) · FAF95 0.722% · FAF99 0.717% · 8,674/1,180,046 in the highest group · 9,523/1,614,200 alleles overall — rare (popmax 0.735%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.735% | 136 |
| Remaining individuals (not grpmax-eligible) | 0.557% | 180 |
| Admixed American | 0.458% | 218 |
| Finnish (not grpmax-eligible) | 0.158% | 633 |
| Middle Eastern | 0.148% | 674 |
| African / African-American | 0.147% | 683 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0101% | 9,869 |
| East Asian | 0.00223% | 44,890 |
| South Asian | 0.0022% | 45,541 |

*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 **552** 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-11-26.

**Submitter consensus:** conflicting (5 Likely benign, 4 Benign).

**Submission history:** 9 submissions (2015–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2015-07-20 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2020-09-08 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2023-02-14 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not specified, not provided, ECEL1-related disorder, ECEL1-related condition, AllHighlyPenetrant, none provided.

## 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 210908). 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.*