# NM_005050.4(ABCD4):c.859G>A (p.Val287Ile)

https://sugi.bio/variant/abcd4-p-val287ile

## Summary

**ABCD4 p.Val287Ile (c.859G>A)** is classified **Uncertain significance** in ABCD4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-24). AlphaMissense: likely benign (0.0852); Very rare (popmax 0.00333%, amr); Associated with methylmalonic acidemia with homocystinuria, type cblJ.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs764251926 · 3 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00333%, amr)

## 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 3 submitters, 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.Val287Ile |
| Coding change (HGVS c.) | c.859G>A |
| MANE Select transcript | [NM_005050](https://www.ncbi.nlm.nih.gov/nuccore/NM_005050) |
| dbSNP | [rs764251926](https://www.ncbi.nlm.nih.gov/snp/rs764251926/) |
| Variant type | single nucleotide variant |
| Location | chr14:74292825-74292825 (GRCh38) |
| ClinVar | [VCV966702](https://www.ncbi.nlm.nih.gov/clinvar/variation/966702/) |

**All HGVS expressions:** `NC_000014.8:g.74759528C>T`, `NC_000014.9:g.74292825C>T`, `NG_032875.1:g.15240G>A`, `NM_001353591.2:c.733G>A`, `NM_001353592.2:c.733G>A`, `NM_001353593.2:c.598G>A`, `NM_001353594.2:c.547G>A`, `NM_001353595.2:c.445G>A`, `NM_001353596.2:c.445G>A`, `NM_001353597.2:c.394G>A`, `NM_001353598.2:c.382G>A`, `NM_001353599.2:c.382G>A`, `NM_001353600.2:c.382G>A`, `NM_001353601.2:c.382G>A`, `NM_001353602.2:c.70G>A`, `NM_001353603.2:c.70G>A`, `NM_001353604.2:c.70G>A`, `NM_001353605.2:c.70G>A`, `NM_001353606.2:c.70G>A`, `NM_001353607.2:c.70G>A`, `NM_001353608.2:c.70G>A`, `NM_001353609.2:c.70G>A`, `NM_001353610.2:c.70G>A`, `NM_005050.4:c.859G>A`, `NM_020324.3:c.382G>A`, `NM_020325.3:c.859G>A`, `NR_003256.3:n.753G>A`, `NR_148466.2:n.781G>A`, `NR_148467.2:n.562G>A`, `NR_148468.2:n.539G>A`, `NR_148469.2:n.786G>A`, `NR_148470.2:n.748G>A`, `NR_148471.2:n.786G>A`, `NR_148472.2:n.835G>A`, `NR_148473.2:n.762G>A`, `NR_148474.2:n.881G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0852)
- REVEL 0.299 (indeterminate)
- SaProt LLR -7.201 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP -1.971, GERP -4.57 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 10.93**. 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 0.99** across the covering region of the MANE Select transcript (74,286,464–74,302,912), spanning 16,448 bp. Chi-square p 0.79. 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 **0.00333%** (amr) · FAF95 0.00111% · FAF99 0.0009% · 2/60,004 in the highest group · 24/1,461,886 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 30,002 |
| South Asian | 0.0022% | 45,541 |
| European (non-Finnish) | 0.00169% | 59,002 |

*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 **287** 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.Val287Ile 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-24.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-18 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-06-07 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-24 |

## 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, Inborn genetic diseases, not provided, none provided, METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblJ TYPE.

## Similar variants {#similar}

Related ABCD4 variant pages (same residue, condition, or type): [ABCD4 p.Val287=](/variant/abcd4-p-val287), [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 2026-10-11); 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 966702). 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.*