# NM_000126.4(ETFA):c.39G>A (p.Ala13=)

https://sugi.bio/variant/etfa-p-ala13

## Summary

**ETFA p.Ala13= (c.39G>A)** is classified **Uncertain significance** in ETFA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-08-12). Very rare (popmax 0.004%, nfe); Associated with multiple acyl-CoA dehydrogenase deficiency.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs776956043 · 3 submitters · 1 linked condition · very rare (popmax 0.004%, nfe)

## 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 3 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.Ala13= |
| Coding change (HGVS c.) | c.39G>A |
| MANE Select transcript | [NM_000126](https://www.ncbi.nlm.nih.gov/nuccore/NM_000126) |
| dbSNP | [rs776956043](https://www.ncbi.nlm.nih.gov/snp/rs776956043/) |
| Variant type | single nucleotide variant |
| Location | chr15:76311350-76311350 (GRCh38) |
| ClinVar | [VCV990296](https://www.ncbi.nlm.nih.gov/clinvar/variation/990296/) |

**All HGVS expressions:** `NC_000015.10:g.76311350C>T`, `NC_000015.9:g.76603691C>T`, `NG_007077.2:g.5120G>A`, `NM_000126.4:c.39G>A`, `NM_001127716.2:c.39G>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 0.25) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.521, GERP 1.29, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.3**. 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 **0.02**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.02**.
  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.*
- Pangolin: Δ**0.47** (loss), gain 0.00 / loss 0.47. 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): grpmax **0.004%** (nfe) · FAF95 0.00306% · FAF99 0.00274% · 46/1,151,360 in the highest group · 47/1,557,556 alleles overall — very rare (popmax 0.004%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.004% | 25,030 |
| Remaining individuals (not grpmax-eligible) | 0.00166% | 60,348 |

*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}


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.


### 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-08-12.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2020–2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-04-19 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-12 |

## 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 II, GA 2, ETHYLMALONIC-ADIPICACIDURIA, GA II, Glutaric aciduria, type 2, Glutaric Acidemia type 2.

## Same-residue context {#hotspot}

Residue **13** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ETFA p.Ala13fs](/variant/etfa-p-ala13fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ETFA variant pages (same residue, condition, or type): [ETFA p.Ala13fs](/variant/etfa-p-ala13fs), [ETFA p.Ala13Thr](/variant/etfa-p-ala13thr), [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).

### 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 990296). 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.*