# NM_005050.4(ABCD4):c.1294del (p.Arg432fs)

https://sugi.bio/variant/abcd4-p-arg432fs

## Summary

**ABCD4 p.Arg432fs (c.1294del)** is classified **Pathogenic** in ABCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-23). Very rare (popmax 0.00203%, nfe); Associated with methylmalonic acidemia with homocystinuria, type cblJ.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1435760575 · 1 submitter · 1 linked condition · very rare (popmax 0.00203%, nfe)

## For patients & families {#patients}

This is a change in the ABCD4 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to methylmalonic acidemia with homocystinuria, type cblJ.

*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, X-linked recessive |
| Age of onset (of this condition) | All ages |
| Diagnostic panels | ABCD4 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Methylmalonic acidemia with homocystinuria** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Microcephaly — Very frequent (99-80%)
- Retinopathy — Very frequent (99-80%)
- Amblyopia — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Lethargy — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012621/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCD4](https://sugi.bio/atlas/gene/ABCD4/) |
| Protein change (HGVS p.) | p.Arg432fs |
| Coding change (HGVS c.) | c.1294del |
| MANE Select transcript | [NM_005050](https://www.ncbi.nlm.nih.gov/nuccore/NM_005050) |
| dbSNP | [rs1435760575](https://www.ncbi.nlm.nih.gov/snp/rs1435760575/) |
| Variant type | Deletion |
| Location | chr14:74290324-74290324 (GRCh38) |
| ClinVar | [VCV1069117](https://www.ncbi.nlm.nih.gov/clinvar/variation/1069117/) |

**All HGVS expressions:** `NC_000014.8:g.74757028del`, `NC_000014.9:g.74290325del`, `NG_032875.1:g.17741del`, `NM_001353591.2:c.1168del`, `NM_001353592.2:c.1168del`, `NM_001353593.2:c.1033del`, `NM_001353594.2:c.982del`, `NM_001353595.2:c.880del`, `NM_001353596.2:c.880del`, `NM_001353597.2:c.829del`, `NM_001353598.2:c.817del`, `NM_001353599.2:c.817del`, `NM_001353600.2:c.817del`, `NM_001353601.2:c.817del`, `NM_001353602.2:c.505del`, `NM_001353603.2:c.505del`, `NM_001353604.2:c.505del`, `NM_001353605.2:c.505del`, `NM_001353606.2:c.505del`, `NM_001353607.2:c.505del`, `NM_001353608.2:c.505del`, `NM_001353609.2:c.505del`, `NM_001353610.2:c.505del`, `NM_005050.4:c.1294del`, `NM_020324.3:c.817del`, `NM_020325.3:c.1294del`, `NR_003256.3:n.1188del`, `NR_148466.2:n.1216del`, `NR_148467.2:n.997del`, `NR_148468.2:n.974del`, `NR_148469.2:n.1221del`, `NR_148470.2:n.1183del`, `NR_148471.2:n.1221del`, `NR_148472.2:n.1270del`, `NR_148473.2:n.1197del`, `NR_148474.2:n.1316del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 (below), not from a missing predictor score.
- Conservation: phyloP 7.491, GERP 2.63, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.772, pLI 4.0217e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 12 of 19**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 33.0**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00203%** (nfe) · FAF95 0.00138% · FAF99 0.00116% · 24/1,180,050 in the highest group · 28/1,614,048 alleles overall — very rare (popmax 0.00203%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,622 |
| European (non-Finnish) (grpmax) | 0.00203% | 49,169 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**ABCD4** population constraint: LOEUF 0.772, pLI 4.0217e-10, missense-Z 0.53147. *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):

- **methylmalonic acidemia with homocystinuria, type cblJ** — Moderate (AR)

## Protein context {#protein}

Residue **432** lies in a UniProt-annotated variant site (in mahcj; decreases interaction with lmbd1. does not affect lysosomal subcellular location. decreases atpase activity); the abc transporter domain.

AlphaFold model confidence (whole protein): pLDDT 87.18, 60% of residues very-high.

**4 experimental structure(s)** (PDB): [24VC](https://www.rcsb.org/structure/24VC), [24VD](https://www.rcsb.org/structure/24VD), [24VE](https://www.rcsb.org/structure/24VE), [6JBJ](https://www.rcsb.org/structure/6JBJ).

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

*Describes the biological roles of ABCD4 (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:** ABCD4's established molecular role includes ABC-type vitamin B12 transporter activity. p.Arg432fs falls in the abc transporter domain. In Reactome, ABCD4 is annotated in disease pathway(s) including **Defective ABCD4 causes MAHCJ**.

**Disease mechanism (Reactome):** ABCD4 loss or alteration is curated in [Defective ABCD4 causes MAHCJ](https://reactome.org/content/detail/R-HSA-5683329).

### Pathways affected {#pathways}

ABCD4 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCD4 causes MAHCJ](https://reactome.org/content/detail/R-HSA-5683329) | curated |
| [Transport of RCbl within the body](https://reactome.org/content/detail/R-HSA-9758890) | curated |
| [Uptake of dietary cobalamins into enterocytes](https://reactome.org/content/detail/R-HSA-9758881) | curated |

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

**Molecular function:** ABC-type vitamin B12 transporter activity, identical protein binding.

**Biological process:** cobalamin metabolic process, cobalamin transport.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-08-23.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-08-23 |

## Associated conditions {#conditions}

[methylmalonic acidemia with homocystinuria, type cblJ](https://sugi.bio/atlas/disease/methylmalonic-acidemia-with-homocystinuria-type-cblj/).

**Reported phenotype names (ClinVar):** Methylmalonic acidemia with homocystinuria, type cblJ, METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblJ TYPE.

## Same-residue context {#hotspot}

Residue **432** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ABCD4 p.Arg432Gln](/variant/abcd4-p-arg432gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ABCD4 variant pages (same residue, condition, or type): [ABCD4 p.Arg432Gln](/variant/abcd4-p-arg432gln), [ABCD4 p.Ala237fs](/variant/abcd4-p-ala237fs), [ABCD4 p.Trp377fs](/variant/abcd4-p-trp377fs), [ABCD4 c.669-11_669-8del](/variant/abcd4-c-669-minus-11-669-minus-8del), [ABCD4 p.Arg125fs](/variant/abcd4-p-arg125fs), [ABCD4 p.Gln101fs](/variant/abcd4-p-gln101fs), [ABCD4 p.Gln215fs](/variant/abcd4-p-gln215fs), [ABCD4 p.Leu44fs](/variant/abcd4-p-leu44fs).

### 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 1069117). 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.*