# NM_001609.4(ACADSB):c.202G>T (p.Val68Phe)

https://sugi.bio/variant/acadsb-p-val68phe

## Summary

**ACADSB p.Val68Phe (c.202G>T)** is classified **Uncertain significance** in ACADSB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-14). AlphaMissense: ambiguous (0.4302); Ultra-rare (popmax 0.0195%, nfe); Associated with 2-methylbutyryl-CoA dehydrogenase deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs144894218 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · ultra-rare (popmax 0.0195%, nfe)

## For patients & families {#patients}

This is a change in the ACADSB gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to 2-methylbutyryl-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 | ACADSB is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of 2-methylbutyryl-CoA dehydrogenase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Elevated circulating C5 acylcarnitine concentration — Frequent (79-30%)
- 2-ethylhydracylic aciduria — Frequent (79-30%)
- Seizure — Occasional (29-5%)
- Hypotonia — Occasional (29-5%)
- Global developmental delay — Occasional (29-5%)
- Failure to thrive in infancy — Occasional (29-5%)
- Microcephaly — Very rare (<4-1%)
- Autism — Very rare (<4-1%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010322/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACADSB](https://sugi.bio/atlas/gene/ACADSB/) |
| Protein change (HGVS p.) | p.Val68Phe |
| Coding change (HGVS c.) | c.202G>T |
| MANE Select transcript | [NM_001609](https://www.ncbi.nlm.nih.gov/nuccore/NM_001609) |
| dbSNP | [rs144894218](https://www.ncbi.nlm.nih.gov/snp/rs144894218/) |
| Variant type | single nucleotide variant |
| Location | chr10:123034515-123034515 (GRCh38) |
| ClinVar | [VCV1358968](https://www.ncbi.nlm.nih.gov/clinvar/variation/1358968/) |

**All HGVS expressions:** `LRG_451:g.30603G>T`, `NC_000010.10:g.124794031G>T`, `NC_000010.11:g.123034515G>T`, `NG_008003.1:g.30603G>T`, `NM_001330174.3:c.-4G>T`, `NM_001609.4:c.202G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **ambiguous** (0.4302) — no call either way
- REVEL 0.892 (moderately pathogenic-leaning)
- SaProt LLR -8.8 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense makes no call
- Conservation: phyloP 9.439, GERP 2.27, phastCons 1 — highly conserved
- CADD: **PHRED 29.9**. 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 1.04** across the covering region of the MANE Select transcript (123,009,030–123,053,762), spanning 44,732 bp. Chi-square p 0.39. 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 (gnomAD v4.1): grpmax **0.0195%** (nfe) · FAF95 0.0174% · FAF99 0.0166% · 230/1,179,680 in the highest group · 232/1,606,470 alleles overall — ultra-rare (popmax 0.0195%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0195% | 5,129 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,220 |

*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}

**ACADSB** population constraint: LOEUF 0.891, pLI 7.245e-07, missense-Z -0.10091; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (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):

- **2-methylbutyryl-CoA dehydrogenase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **68** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 91.47, 88% of residues very-high.

**1 experimental structure(s)** (PDB): [2JIF](https://www.rcsb.org/structure/2JIF).

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

*Describes the biological roles of ACADSB (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:** ACADSB's established molecular role includes short-chain 2-methyl fatty acyl-CoA dehydrogenase activity.


### Pathways affected {#pathways}

ACADSB 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 |

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

**Molecular function:** short-chain 2-methyl fatty acyl-CoA dehydrogenase activity, short-chain fatty acyl-CoA dehydrogenase activity, identical protein binding.

**Biological process:** L-isoleucine catabolic process, fatty acid metabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-14.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-14 |

## Associated conditions {#conditions}

[2-methylbutyryl-CoA dehydrogenase deficiency](https://sugi.bio/atlas/disease/2-methylbutyryl-coa-dehydrogenase-deficiency/).

**Reported phenotype names (ClinVar):** Deficiency of 2-methylbutyryl-CoA dehydrogenase, 2-methylbutyrylglycinuria, 2-methylbutyryl-CoA dehydrogenase deficiency, SBCAD deficiency, 2-methylbutyric aciduria, Short branched-chain acyl-CoA dehydrogenase deficiency.

## Similar variants {#similar}

Related ACADSB variant pages (same residue, condition, or type): [ACADSB c.1128+1G>A](/variant/acadsb-c-1128-plus-1g-a), [ACADSB c.1228+1G>A](/variant/acadsb-c-1228-plus-1g-a), [ACADSB c.303+3A>G](/variant/acadsb-c-303-plus-3a-g), [ACADSB p.Cys308Tyr](/variant/acadsb-p-cys308tyr), [ACADSB p.Gln99Ter](/variant/acadsb-p-gln99ter), [ACADSB p.Glu387Lys](/variant/acadsb-p-glu387lys), [ACADSB p.Gly410Ser](/variant/acadsb-p-gly410ser), [ACADSB p.Met389Val](/variant/acadsb-p-met389val).

### 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 1358968). 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.*