# NM_014384.3(ACAD8):c.408C>T (p.Phe136=)

https://sugi.bio/variant/acad8-p-phe136

## Summary

**ACAD8 p.Phe136= (c.408C>T)** is classified **Benign/Likely benign** in ACAD8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-04-27). Ultra-rare (popmax 0.0165%, mid); Associated with isobutyryl-CoA dehydrogenase deficiency.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs143408080 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the ACAD8 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to isobutyryl-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 |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ACAD8 is a diagnostic-grade gene on 6 Genomics England panels |

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

- Dicarboxylic aciduria — Frequent (79-30%)
- Decreased circulating carnitine concentration — Frequent (79-30%)
- Elevated plasma acylcarnitine levels — Frequent (79-30%)
- Delayed speech and language development — Occasional (29-5%)
- Hypotonia — Occasional (29-5%)
- Pulmonic stenosis — Occasional (29-5%)
- Dilated cardiomyopathy — Occasional (29-5%)
- Dehydration — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010223/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACAD8](https://sugi.bio/atlas/gene/ACAD8/) |
| Protein change (HGVS p.) | p.Phe136= |
| Coding change (HGVS c.) | c.408C>T |
| MANE Select transcript | [NM_014384](https://www.ncbi.nlm.nih.gov/nuccore/NM_014384) |
| dbSNP | [rs143408080](https://www.ncbi.nlm.nih.gov/snp/rs143408080/) |
| Variant type | single nucleotide variant |
| Location | chr11:134258542-134258542 (GRCh38) |
| ClinVar | [VCV741347](https://www.ncbi.nlm.nih.gov/clinvar/variation/741347/) |

**All HGVS expressions:** `LRG_448:g.10003C>T`, `LRG_448t1:c.408C>T`, `NC_000011.10:g.134258542C>T`, `NC_000011.9:g.134128436C>T`, `NG_015842.1:g.10003C>T`, `NM_014384.3:c.408C>T`

## 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 **acceptor loss** (Δ 0.24) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.042, GERP -2.83, phastCons 0.905 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.206**. 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 **0.24**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 27 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  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**0.29** (loss), gain 0.00 / loss 0.29. 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 **0.0165%** (mid) · FAF95 0.00867% · FAF99 0.00812% · 1/6,062 in the highest group · 146/1,613,728 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| African / African-American | 0.0147% | 6,815 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,928 |
| European (non-Finnish) | 0.0102% | 9,832 |
| East Asian | 0.00669% | 14,957 |
| Admixed American | 0.00333% | 29,999 |
| South Asian | 0.0022% | 45,511 |

*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}

**ACAD8** population constraint: LOEUF 1.11, pLI 6.951e-14, missense-Z 0.88893; 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):

- **isobutyryl-CoA dehydrogenase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **136** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 94.19, 93% of residues very-high.

**1 experimental structure(s)** (PDB): [1RX0](https://www.rcsb.org/structure/1RX0).

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

*Describes the biological roles of ACAD8 (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}

ACAD8 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Branched-chain amino acid catabolism](https://reactome.org/content/detail/R-HSA-70895) | curated |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-04-27.

**Submitter consensus:** conflicting (1 Benign, 1 Likely benign).

**Submission history:** 2 submissions (2015–2018); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2018-04-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Deficiency of isobutyryl-CoA dehydrogenase, not provided, none provided, ACYL-CoA DEHYDROGENASE FAMILY, MEMBER 8, DEFICIENCY OF, IBD DEFICIENCY, ACAD8 DEFICIENCY.

## Similar variants {#similar}

Related ACAD8 variant pages (same residue, condition, or type): [ACAD8 p.Phe136Leu](/variant/acad8-p-phe136leu), [ACAD8 p.Arg206Ter](/variant/acad8-p-arg206ter), [ACAD8 p.Arg296Ter](/variant/acad8-p-arg296ter), [ACAD8 p.Gly377Ser](/variant/acad8-p-gly377ser), [ACAD8 p.Gly96Ser](/variant/acad8-p-gly96ser), [ACAD8 p.Met128Ile](/variant/acad8-p-met128ile), [ACAD8 p.Met1Thr](/variant/acad8-p-met1thr), [ACAD8 c.841+6A>C](/variant/acad8-c-841-plus-6a-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 741347). 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.*