# NM_005689.4(ABCB6):c.1123C>T (p.Arg375Trp)

https://sugi.bio/variant/abcb6-p-arg375trp

## Summary

**ABCB6 p.Arg375Trp (c.1123C>T)** is classified **Conflicting classifications of pathogenicity** in ABCB6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-07-10). AlphaMissense: likely pathogenic (0.8942); Very rare (popmax 0.00111%, sas); Associated with dyschromatosis universalis hereditaria 3.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs764893806 · 3 submitters · 3 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00111%, sas)

## For patients & families {#patients}

This is a change in the ABCB6 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to dyschromatosis universalis hereditaria 3.

*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 dominant, Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy |
| Diagnostic panels | ABCB6 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Dyschromatosis universalis hereditaria** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypermelanotic macule — Very frequent (99-80%)
- Hypopigmented skin patches — Very frequent (99-80%)
- Spotty hypopigmentation — Very frequent (99-80%)
- Macule — Very frequent (99-80%)
- Hearing impairment — Frequent (79-30%)
- Cutaneous photosensitivity — Frequent (79-30%)
- Freckling — Frequent (79-30%)
- Multiple cafe-au-lait spots — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015959/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCB6](https://sugi.bio/atlas/gene/ABCB6/) |
| Protein change (HGVS p.) | p.Arg375Trp |
| Coding change (HGVS c.) | c.1123C>T |
| MANE Select transcript | [NM_005689](https://www.ncbi.nlm.nih.gov/nuccore/NM_005689) |
| dbSNP | [rs764893806](https://www.ncbi.nlm.nih.gov/snp/rs764893806/) |
| Variant type | single nucleotide variant |
| Location | chr2:219216028-219216028 (GRCh38) |
| ClinVar | [VCV218180](https://www.ncbi.nlm.nih.gov/clinvar/variation/218180/) |

**All HGVS expressions:** `LRG_824:g.7963C>T`, `LRG_824t1:c.1123C>T`, `NC_000002.11:g.220080750G>A`, `NC_000002.12:g.219216028G>A`, `NG_032110.1:g.7963C>T`, `NM_001349828.2:c.985C>T`, `NM_005689.4:c.1123C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.8942)
- REVEL 0.842 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.568 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 5.658, GERP 2.05, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 29.4**. 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 0.96** across the covering region of the MANE Select transcript (219,209,941–219,218,673), spanning 8,732 bp. Chi-square p 0.15. 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 **0.00111%** (sas) · 1/90,004 in the highest group · 2/1,447,846 alleles overall — very rare (popmax 0.00111%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00111% | 90,004 |
| European (non-Finnish) | 8.54e-05% | 1,171,580 |

*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}

**ABCB6** population constraint: LOEUF 0.984, pLI 2.0017e-25, missense-Z 0.90031. *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):

- **microphthalmia, isolated, with coloboma 7** — Limited (AD)
- **dyschromatosis universalis hereditaria 3** — Moderate (AD)

## Protein context {#protein}

Residue **375** lies in the abc transmembrane type-1 domain; a UniProt-annotated variant site (in pshk2); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 83.17, 43% of residues very-high.

**16 experimental structure(s)** (PDB): [3NH6](https://www.rcsb.org/structure/3NH6), [3NH9](https://www.rcsb.org/structure/3NH9), [3NHA](https://www.rcsb.org/structure/3NHA), [3NHB](https://www.rcsb.org/structure/3NHB), [7D7N](https://www.rcsb.org/structure/7D7N), [7D7R](https://www.rcsb.org/structure/7D7R) — incl. mutant structure 8K7B.

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

*Describes the biological roles of ABCB6 (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:** ABCB6's established molecular role includes ATP binding. p.Arg375Trp falls in the abc transmembrane type-1 domain. In Reactome, ABCB6 is annotated in disease pathway(s) including **Defective ABCB6 causes MCOPCB7**.

**Disease mechanism (Reactome):** ABCB6 loss or alteration is curated in [Defective ABCB6 causes MCOPCB7](https://reactome.org/content/detail/R-HSA-5683371).

### Pathways affected {#pathways}

ABCB6 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCB6 causes MCOPCB7](https://reactome.org/content/detail/R-HSA-5683371) | other |
| [Mitochondrial ABC transporters](https://reactome.org/content/detail/R-HSA-1369007) | other |

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

**Molecular function:** ATP binding, ABC-type heme transporter activity, efflux transmembrane transporter activity, ATP hydrolysis activity, heme binding, tetrapyrrole binding.

**Biological process:** porphyrin-containing compound metabolic process, porphyrin-containing compound biosynthetic process, brain development, heme transport, tetrapyrrole metabolic process, heme transmembrane transport.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-07-10.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 3 submissions (2013–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2013-01-01 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-04-01 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-10 |

## Associated conditions {#conditions}

[dyschromatosis universalis hereditaria 3](https://sugi.bio/atlas/disease/dyschromatosis-universalis-hereditaria-3/), [familial pseudohyperkalemia](https://sugi.bio/atlas/disease/familial-pseudohyperkalemia/), [microphthalmia, isolated, with coloboma 7](https://sugi.bio/atlas/disease/microphthalmia-isolated-with-coloboma-7/).

**Reported phenotype names (ClinVar):** Dyschromatosis universalis hereditaria 3, Familial pseudohyperkalemia, Langereis blood group, Microphthalmia, isolated, with coloboma 7, not provided, none provided, MICROPHTHALMIA/COLOBOMA 7, ocular coloboma, Pseudohyperkalemia, familial, 2, due to red cell leak, PSEUDOHYPERKALEMIA EAST LONDON.

## Same-residue context {#hotspot}

Residue **375** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ABCB6 p.Arg375Gln](/variant/abcb6-p-arg375gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ABCB6 variant pages (same residue, condition, or type): [ABCB6 p.Arg375Gln](/variant/abcb6-p-arg375gln), [ABCB6 p.Ala57Thr](/variant/abcb6-p-ala57thr), [ABCB6 p.Arg723Gln](/variant/abcb6-p-arg723gln), [ABCB6 p.Arg739Cys](/variant/abcb6-p-arg739cys), [ABCB6 p.Glu220Val](/variant/abcb6-p-glu220val), [ABCB6 p.Gly317Trp](/variant/abcb6-p-gly317trp), [ABCB6 p.Phe565Ser](/variant/abcb6-p-phe565ser), [ABCB6 c.688-9C>T](/variant/abcb6-c-688-minus-9c-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 218180). 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.*