# NM_004826.4(ECEL1):c.1155G>A (p.Val385=)

https://sugi.bio/variant/ecel1-p-val385

## Summary

**ECEL1 p.Val385= (c.1155G>A)** is classified **Likely pathogenic** in ECEL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-14). Very rare (popmax 0.000657%); Associated with ECEL1-related disorders.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.000657%)

## For patients & families {#patients}

This is a change in the ECEL1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to ECEL1-related disorders.

*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.Val385= |
| Coding change (HGVS c.) | c.1155G>A |
| MANE Select transcript | [NM_004826](https://www.ncbi.nlm.nih.gov/nuccore/NM_004826) |
| Variant type | single nucleotide variant |
| Location | chr2:232484501-232484501 (GRCh38) |
| ClinVar | [VCV4960552](https://www.ncbi.nlm.nih.gov/clinvar/variation/4960552/) |

**All HGVS expressions:** `NC_000002.11:g.233349211C>T`, `NC_000002.12:g.232484501C>T`, `NG_034065.1:g.8359G>A`, `NM_001290787.2:c.1155G>A`, `NM_004826.4:c.1155G>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 gain** (Δ 0.63) — consistent with the pathogenic call
- Conservation: phyloP 4.654, GERP 0.598, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 21.1**. 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 **0.25**, acceptor gain **0.00**, donor gain **0.63**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.63**.
- Pangolin: Δ**0.76** (gain), gain 0.76 / loss 0.70. 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): global (via dbSNP) **0.000657%** · 1/152,228 alleles overall — very rare (popmax 0.000657%).

*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 **385** lies in the peptidase m13 domain.

AlphaFold model confidence (whole protein): pLDDT 88.62, 77% of residues very-high.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-14.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-06-14 |

## Associated conditions {#conditions}

[ECEL1-related disorders](https://sugi.bio/atlas/disease/ecel1-related-disorders/).

**Reported phenotype names (ClinVar):** ECEL1-related disorders.

## Similar variants {#similar}

Related ECEL1 variant pages (same residue, condition, or type): [ECEL1 p.Val385Met](/variant/ecel1-p-val385met), [ECEL1 p.Gln435Ter](/variant/ecel1-p-gln435ter), [ECEL1 p.Thr615Pro](/variant/ecel1-p-thr615pro), [ECEL1 p.Tyr618Ter](/variant/ecel1-p-tyr618ter), [ECEL1 p.Arg404Cys](/variant/ecel1-p-arg404cys), [ECEL1 p.Leu733Pro](/variant/ecel1-p-leu733pro), [ECEL1 p.Arg663Trp](/variant/ecel1-p-arg663trp), [ECEL1 c.2228+4T>A](/variant/ecel1-c-2228-plus-4t-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 4960552). 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.*