# NM_005050.4(ABCD4):c.384G>A (p.Ala128=)

https://sugi.bio/variant/abcd4-p-ala128

## Summary

**ABCD4 p.Ala128= (c.384G>A)** is classified **Uncertain significance** in ABCD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-08). Ultra-rare (popmax 0.0214%, afr); Associated with methylmalonic acidemia with homocystinuria, type cblJ.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs376619713 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0214%, afr)

## For patients & families {#patients}

This is a change in the ABCD4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Ala128= |
| Coding change (HGVS c.) | c.384G>A |
| MANE Select transcript | [NM_005050](https://www.ncbi.nlm.nih.gov/nuccore/NM_005050) |
| dbSNP | [rs376619713](https://www.ncbi.nlm.nih.gov/snp/rs376619713/) |
| Variant type | single nucleotide variant |
| Location | chr14:74297971-74297971 (GRCh38) |
| ClinVar | [VCV2162590](https://www.ncbi.nlm.nih.gov/clinvar/variation/2162590/) |

**All HGVS expressions:** `NC_000014.8:g.74764674C>T`, `NC_000014.9:g.74297971C>T`, `NG_032875.1:g.10094G>A`, `NM_001353591.2:c.384G>A`, `NM_001353592.2:c.384G>A`, `NM_001353593.2:c.123G>A`, `NM_001353594.2:c.123G>A`, `NM_001353595.2:c.-26G>A`, `NM_001353596.2:c.-26G>A`, `NM_001353597.2:c.-26G>A`, `NM_001353598.2:c.-94G>A`, `NM_001353599.2:c.-52-1522G>A`, `NM_001353600.2:c.-94G>A`, `NM_001353601.2:c.-52-1522G>A`, `NM_001353602.2:c.-306G>A`, `NM_001353603.2:c.-311G>A`, `NM_001353604.2:c.-269-1522G>A`, `NM_001353605.2:c.-311G>A`, `NM_001353606.2:c.-311G>A`, `NM_001353607.2:c.-311G>A`, `NM_001353608.2:c.-264-1522G>A`, `NM_001353609.2:c.-311G>A`, `NM_001353610.2:c.-311G>A`, `NM_005050.4:c.384G>A`, `NM_020323.1:c.255G>A`, `NM_020324.3:c.-52-1522G>A`, `NM_020325.3:c.384G>A`, `NR_003256.3:n.278G>A`, `NR_148466.2:n.406G>A`, `NR_148468.2:n.159G>A`, `NR_148469.2:n.406G>A`, `NR_148470.2:n.278G>A`, `NR_148471.2:n.406G>A`, `NR_148473.2:n.287G>A`, `NR_148474.2:n.406G>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 0.45) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.042, GERP 0.134, phastCons 0.81 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 15.08**. 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 **0.45**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 5 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.*
- Population frequency (gnomAD v4.1): grpmax **0.0214%** (afr) · FAF95 0.0133% · FAF99 0.0109% · 16/74,910 in the highest group · 32/1,613,894 alleles overall — ultra-rare (popmax 0.0214%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0214% | 4,682 |
| South Asian | 0.00549% | 18,214 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,236 |
| European (non-Finnish) | 0.000763% | 131,109 |

*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 **128** lies in the abc transmembrane type-1 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.Ala128= falls in the abc transmembrane type-1 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-08.

**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 | 2023-05-08 |

## 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.

## Similar variants {#similar}

Related ABCD4 variant pages (same residue, condition, or type): [ABCD4 p.Ala128Val](/variant/abcd4-p-ala128val), [ABCD4 c.542+1G>T](/variant/abcd4-c-542-plus-1g-t), [ABCD4 p.Arg432Gln](/variant/abcd4-p-arg432gln), [ABCD4 p.Asn141Lys](/variant/abcd4-p-asn141lys), [ABCD4 p.Gln530Ter](/variant/abcd4-p-gln530ter), [ABCD4 p.Tyr176Ter](/variant/abcd4-p-tyr176ter), [ABCD4 c.1028+5G>A](/variant/abcd4-c-1028-plus-5g-a), [ABCD4 c.425+6C>T](/variant/abcd4-c-425-plus-6c-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2162590). 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.*