# NM_001398.3(ECH1):c.643G>T (p.Val215Phe)

https://sugi.bio/variant/ech1-p-val215phe

## Summary

**ECH1 p.Val215Phe (c.643G>T)** is classified **Uncertain significance** in ECH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-05). AlphaMissense: ambiguous (0.3538); Very rare (popmax 6.84e-05%).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 6.84e-05%)

## For patients & families {#patients}

This is a change in the ECH1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [ECH1](https://sugi.bio/atlas/gene/ECH1/) |
| Protein change (HGVS p.) | p.Val215Phe |
| Coding change (HGVS c.) | c.643G>T |
| MANE Select transcript | [NM_001398](https://www.ncbi.nlm.nih.gov/nuccore/NM_001398) |
| Variant type | single nucleotide variant |
| Location | chr19:38816469-38816469 (GRCh38) |
| ClinVar | [VCV3506456](https://www.ncbi.nlm.nih.gov/clinvar/variation/3506456/) |

**All HGVS expressions:** `NC_000019.10:g.38816469C>A`, `NC_000019.9:g.39307109C>A`, `NM_001398.3:c.643G>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; SaProt calls this damaging; REVEL does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.3538) — no call either way
- REVEL 0.242 (benign-leaning)
- SaProt LLR -12.847 (damaging)
- → **In-silico consensus:** SaProt calls this damaging; REVEL does not; AlphaMissense makes no call
- SpliceAI predicts **donor loss** (Δ 0.31) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -2.137, GERP -4.18 — fast-evolving / accelerated position
- CADD: **PHRED 18.16**. 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.*
- Regional missense constraint: **o/e 1.03** across the covering region of the MANE Select transcript (38,815,616–38,831,772), spanning 16,156 bp. Chi-square p 0.49. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.31**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.31**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): global (via dbSNP) **6.84e-05%** · 1/1,461,864 alleles overall — very rare (popmax 6.84e-05%).

*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 **215** 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-05.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-05 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## 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 3506456). 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.*