# NM_000126.4(ETFA):c.457G>C (p.Ala153Pro)

https://sugi.bio/variant/etfa-p-ala153pro

## Summary

**ETFA p.Ala153Pro (c.457G>C)** is classified **Uncertain significance** in ETFA (ClinVar, Single submitter, 2 submitters; last evaluated 2019-09-24). AlphaMissense: likely pathogenic (0.9835); Very rare (popmax 0.00134%, afr); Associated with multiple acyl-CoA dehydrogenase deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1398343360 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the ETFA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to multiple acyl-CoA dehydrogenase deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (United States) |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ETFA is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of Multiple acyl-CoA dehydrogenase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypotonia — Frequent (79-30%)
- Hypoglycemia — Frequent (79-30%)
- Elevated circulating creatine kinase concentration — Frequent (79-30%)
- Myalgia — Frequent (79-30%)
- Proximal muscle weakness — Frequent (79-30%)
- Exercise-induced muscle fatigue — Frequent (79-30%)
- Phenotypic abnormality — Occasional (29-5%)
- Wide anterior fontanel — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006523/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ETFA](https://sugi.bio/atlas/gene/ETFA/) |
| Protein change (HGVS p.) | p.Ala153Pro |
| Coding change (HGVS c.) | c.457G>C |
| MANE Select transcript | [NM_000126](https://www.ncbi.nlm.nih.gov/nuccore/NM_000126) |
| dbSNP | [rs1398343360](https://www.ncbi.nlm.nih.gov/snp/rs1398343360/) |
| Variant type | single nucleotide variant |
| Location | chr15:76286476-76286476 (GRCh38) |
| ClinVar | [VCV947016](https://www.ncbi.nlm.nih.gov/clinvar/variation/947016/) |

**All HGVS expressions:** `NC_000015.10:g.76286476C>G`, `NC_000015.9:g.76578817C>G`, `NG_007077.2:g.29994G>C`, `NM_000126.4:c.457G>C`, `NM_001127716.2:c.310G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9835)
- REVEL 0.874 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.235 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.689, GERP 1.86, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.9**. 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 0.86** across the covering region of the MANE Select transcript (76,216,562–76,311,388), spanning 94,826 bp. Chi-square p 0.0051. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.41 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 **0.00134%** (afr) · 1/74,740 in the highest group · 1/152,192 alleles overall — very rare (popmax 0.00134%, afr).

*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}

**ETFA** population constraint: LOEUF 1.166, pLI 0.0029774, missense-Z 0.7966. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **multiple acyl-CoA dehydrogenase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **153** lies in the 'domain i' region; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 94.00, 91% of residues very-high.

**4 experimental structure(s)** (PDB): [1EFV](https://www.rcsb.org/structure/1EFV), [1T9G](https://www.rcsb.org/structure/1T9G), [2A1T](https://www.rcsb.org/structure/2A1T), [2A1U](https://www.rcsb.org/structure/2A1U) — incl. mutant structure 2A1U.

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

*Describes the biological roles of ETFA (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.*

**How this variant is thought to act:** ETFA's established molecular role includes electron transfer activity. p.Ala153Pro falls in the domain i region.


### Pathways affected {#pathways}

ETFA participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Respiratory electron transport](https://reactome.org/content/detail/R-HSA-611105) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** electron transfer activity, oxidoreductase activity, flavin adenine dinucleotide binding.

**Biological process:** amino acid catabolic process, respiratory electron transport chain, fatty acid beta-oxidation using acyl-CoA dehydrogenase.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-09-24.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2019–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-09-24 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2021-02-25 |

## Associated conditions {#conditions}

[multiple acyl-CoA dehydrogenase deficiency](https://sugi.bio/atlas/disease/multiple-acyl-coa-dehydrogenase-deficiency/).

**Reported phenotype names (ClinVar):** Multiple acyl-CoA dehydrogenase deficiency, Glutaric acidemia type 2A, ETHYLMALONIC-ADIPICACIDURIA, GA II, Glutaric aciduria, type 2, Glutaric Acidemia type 2, Glutaric acidemia type II, GA 2.

## Similar variants {#similar}

Related ETFA variant pages (same residue, condition, or type): [ETFA c.186+1G>A](/variant/etfa-c-186-plus-1g-a), [ETFA c.39+1G>A](/variant/etfa-c-39-plus-1g-a), [ETFA c.451+1G>A](/variant/etfa-c-451-plus-1g-a), [ETFA c.452-2A>G](/variant/etfa-c-452-minus-2a-g), [ETFA c.664+1G>A](/variant/etfa-c-664-plus-1g-a), [ETFA c.665-1G>A](/variant/etfa-c-665-minus-1g-a), [ETFA p.Arg122Lys](/variant/etfa-p-arg122lys), [ETFA p.Arg18Ter](/variant/etfa-p-arg18ter).

### 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 947016). 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.*