# NM_000018.4(ACADVL):c.425T>C (p.Phe142Ser)

https://sugi.bio/variant/acadvl-p-phe142ser

## Summary

**ACADVL p.Phe142Ser (c.425T>C)** is classified **Uncertain significance** in ACADVL (ClinVar, Expert panel, 4 submitters; last evaluated 2022-12-14). AlphaMissense: likely pathogenic (0.8408); Absent from gnomAD v4.1; Associated with very long chain acyl-CoA dehydrogenase deficiency.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs398123088 · 4 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ACADVL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 submitters, and is linked to very long chain 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) | Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 10 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ACADVL is a diagnostic-grade gene on 11 Genomics England panels |

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

- Increased circulating free fatty acid level — Frequent (79-30%)
- Jaundice — Occasional (29-5%)
- Small for gestational age — Occasional (29-5%)
- Ventricular septal defect — Occasional (29-5%)
- Atrial septal defect — Occasional (29-5%)
- Patent foramen ovale — Occasional (29-5%)
- Hypoketotic hypoglycemia — Occasional (29-5%)
- Hypothermia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005508/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACADVL](https://sugi.bio/atlas/gene/ACADVL/) |
| Protein change (HGVS p.) | p.Phe142Ser |
| Coding change (HGVS c.) | c.425T>C |
| MANE Select transcript | [NM_000018](https://www.ncbi.nlm.nih.gov/nuccore/NM_000018) |
| dbSNP | [rs398123088](https://www.ncbi.nlm.nih.gov/snp/rs398123088/) |
| Variant type | single nucleotide variant |
| Location | chr17:7221006-7221006 (GRCh38) |
| ClinVar | [VCV92283](https://www.ncbi.nlm.nih.gov/clinvar/variation/92283/) |

**All HGVS expressions:** `NC_000017.10:g.7124325T>C`, `NC_000017.11:g.7221006T>C`, `NG_007975.1:g.6173T>C`, `NG_008391.2:g.4045A>G`, `NM_000018.4:c.425T>C`, `NM_001033859.3:c.359T>C`, `NM_001270447.2:c.494T>C`, `NM_001270448.2:c.197T>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** (0.8408)
- REVEL 0.944 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.906 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.861, GERP 2.08, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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 1.02** across the covering region of the MANE Select transcript (7,219,985–7,225,094), spanning 5,109 bp. Chi-square p 0.51. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**ACADVL** population constraint: LOEUF 1.077, pLI 2.425e-22, missense-Z 0.10097; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **very long chain acyl-CoA dehydrogenase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **142** lies in the 'catalytic' region; a turn.

AlphaFold model confidence (whole protein): pLDDT 90.65, 85% of residues very-high.

**3 experimental structure(s)** (PDB): [2UXW](https://www.rcsb.org/structure/2UXW), [3B96](https://www.rcsb.org/structure/3B96), [7S7G](https://www.rcsb.org/structure/7S7G).

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

*Describes the biological roles of ACADVL (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:** ACADVL's established molecular role includes acyl-CoA dehydrogenase activity. p.Phe142Ser falls in the catalytic region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Beta oxidation of palmitoyl-CoA to myristoyl-CoA](https://reactome.org/content/detail/R-HSA-77305) | curated |
| [XBP1(S) activates chaperone genes](https://reactome.org/content/detail/R-HSA-381038) | curated |

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

**Molecular function:** acyl-CoA dehydrogenase activity, long-chain fatty acyl-CoA dehydrogenase activity, very-long-chain fatty acyl-CoA dehydrogenase activity, identical protein binding, flavin adenine dinucleotide binding.

**Biological process:** epithelial cell differentiation, fatty acid beta-oxidation using acyl-CoA dehydrogenase.

## Clinical significance {#significance}

**Uncertain significance** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2022-12-14.

**Submitter consensus:** conflicting (2 Likely pathogenic, 2 Uncertain significance).

**Submission history:** 4 submissions (2013–2022); classifications have differed over time.

**ClinGen expert panel:** Uncertain Significance — ACADVL VCEP (very long chain acyl-CoA dehydrogenase deficiency). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM3_Supporting`, `PM2_Supporting`, `PP3`, `PP4`.
*Considered but not met:* `PVS1`, `PS1`, `PM1`, `PP1`, `PM5`, `PM4`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.425T>C variant in ACADVL is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 142 (p.Phe142Ser). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.94, which is  above the threshold 0.75, evidence that correlates with impact to ACADVL function (PP3). At least one patient with this variant displayed organic acidemia and fatty acid oxidation issues, which are highly specific for VLCAD deficiency (PP4, PMID: 27629047, PMID: 28980192). This individual was also reported homozygous for the variant (PMID: 27629047; points=0.5; PM3_supporting). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2,PM3_supporting PP3, PP4
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50048 · approved 2022-12-14 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/3f32f6a5-2276-4bab-b736-853284e9704f).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CENTOGENE GmbH and LLC - Guiding Precision Medicine | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2013-07-31 |
| Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Likely pathogenic | no assertion criteria provided | clinical testing | 2019-01-29 |
| ClinGen ACADVL Variant Curation Expert Panel, ClinGen | Uncertain significance | reviewed by expert panel | curation | 2022-12-14 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Very long chain acyl-CoA dehydrogenase deficiency, not provided, none provided, Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency, VLCAD Deficiency.

## Similar variants {#similar}

Related ACADVL variant pages (same residue, condition, or type): [ACADVL c.1077+1G>A](/variant/acadvl-c-1077-plus-1g-a), [ACADVL c.1077+1G>T](/variant/acadvl-c-1077-plus-1g-t), [ACADVL c.1077+2T>A](/variant/acadvl-c-1077-plus-2t-a), [ACADVL c.1077+2T>C](/variant/acadvl-c-1077-plus-2t-c), [ACADVL c.1182+1G>A](/variant/acadvl-c-1182-plus-1g-a), [ACADVL c.1269+1G>A](/variant/acadvl-c-1269-plus-1g-a), [ACADVL c.1532+1G>A](/variant/acadvl-c-1532-plus-1g-a), [ACADVL c.1532+2T>C](/variant/acadvl-c-1532-plus-2t-c).

### 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 92283). 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.*