# NM_001398.3(ECH1):c.375G>A (p.Ser125=)

https://sugi.bio/variant/ech1-p-ser125

## Summary

**ECH1 p.Ser125= (c.375G>A)** is classified **Benign** in ECH1 (ClinVar, Single submitter, 2 submitters). Common (popmax 27.8%, sas) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Single submitter · rsID rs15570 · 2 submitters · common (popmax 27.8%, sas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the ECH1 gene that is classified as benign — not considered disease-causing, submitted by 2 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 | [ECH1](https://sugi.bio/atlas/gene/ECH1/) |
| Protein change (HGVS p.) | p.Ser125= |
| Coding change (HGVS c.) | c.375G>A |
| MANE Select transcript | [NM_001398](https://www.ncbi.nlm.nih.gov/nuccore/NM_001398) |
| dbSNP | [rs15570](https://www.ncbi.nlm.nih.gov/snp/rs15570/) |
| Variant type | single nucleotide variant |
| Location | chr19:38817550-38817550 (GRCh38) |
| ClinVar | [VCV559112](https://www.ncbi.nlm.nih.gov/clinvar/variation/559112/) |

**All HGVS expressions:** `NC_000019.10:g.38817550C>T`, `NC_000019.9:g.39308190C>T`, `NM_001398.3:c.375G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 27.8%, sas) — too common for a highly-penetrant pathogenic allele.

- **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 -10.218, GERP -3.79 — fast-evolving / accelerated position
- CADD: **PHRED 0.416**. 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 (C>A, Δ0.51 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 **27.8%** (sas) · FAF95 27.6% · FAF99 27.4% · 25,296/90,848 in the highest group · 225,992/1,608,500 alleles overall — common (popmax 27.8%, sas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 27.8% | 4 |
| Middle Eastern | 20.7% | 5 |
| African / African-American | 19.7% | 5 |
| Amish (not grpmax-eligible) | 14.8% | 7 |
| Remaining individuals (not grpmax-eligible) | 14.1% | 7 |
| European (non-Finnish) | 13.1% | 8 |
| Ashkenazi Jewish (not grpmax-eligible) | 12.7% | 8 |
| Admixed American | 12.1% | 8 |
| Finnish (not grpmax-eligible) | 10.4% | 10 |
| East Asian | 9.57% | 10 |

*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}

**ECH1** population constraint: LOEUF 1.083, pLI 1.5281e-09, missense-Z -0.16112. *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 **125** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 88.61, 81% of residues very-high.

**2 experimental structure(s)** (PDB): [2VRE](https://www.rcsb.org/structure/2VRE), [8SK6](https://www.rcsb.org/structure/8SK6).

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

*Describes the biological roles of ECH1 (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.*


### Pathways affected {#pathways}

ECH1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | electronic |

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2015); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | no assertion criteria provided | clinical testing | 2015-10-26 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

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

## Similar variants {#similar}

Related ECH1 variant pages (same residue, condition, or type): [ECH1 p.Lys95Arg](/variant/ech1-p-lys95arg), [ECH1 p.Ala226Thr](/variant/ech1-p-ala226thr), [ECH1 p.Ala237Val](/variant/ech1-p-ala237val), [ECH1 p.Ala259Thr](/variant/ech1-p-ala259thr), [ECH1 p.Ala3Thr](/variant/ech1-p-ala3thr), [ECH1 p.Ala50Thr](/variant/ech1-p-ala50thr), [ECH1 p.Arg137Trp](/variant/ech1-p-arg137trp), [ECH1 p.Arg143His](/variant/ech1-p-arg143his).

### 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 559112). 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.*