# NM_005689.4(ABCB6):c.46C>T (p.Pro16Ser)

https://sugi.bio/variant/abcb6-p-pro16ser

## Summary

**ABCB6 p.Pro16Ser (c.46C>T)** is classified **Uncertain significance** in ABCB6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-12). AlphaMissense: likely benign (0.0924); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ABCB6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [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.Pro16Ser |
| Coding change (HGVS c.) | c.46C>T |
| MANE Select transcript | [NM_005689](https://www.ncbi.nlm.nih.gov/nuccore/NM_005689) |
| Variant type | single nucleotide variant |
| Location | chr2:219218628-219218628 (GRCh38) |
| ClinVar | [VCV4563834](https://www.ncbi.nlm.nih.gov/clinvar/variation/4563834/) |

**All HGVS expressions:** `LRG_824:g.5363C>T`, `LRG_824t1:c.46C>T`, `NC_000002.11:g.220083350G>A`, `NC_000002.12:g.219218628G>A`, `NG_032110.1:g.5363C>T`, `NG_097634.1:g.554G>A`, `NM_001349828.2:c.46C>T`, `NM_005689.4:c.46C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0924)
- REVEL 0.239 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.588 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 9.817, GERP 2.02, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.6**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.29 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **16** lies in the 'required for atpase activity' region; the 'required for the lysosomal targeting' region.

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.Pro16Ser falls in the required for atpase activity region. 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-12 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related ABCB6 variant pages (same residue, condition, or type): [ABCB6 p.Ala57Thr](/variant/abcb6-p-ala57thr), [ABCB6 p.Ala66Thr](/variant/abcb6-p-ala66thr), [ABCB6 p.Arg439Cys](/variant/abcb6-p-arg439cys), [ABCB6 p.Arg450Gln](/variant/abcb6-p-arg450gln), [ABCB6 p.Arg685His](/variant/abcb6-p-arg685his), [ABCB6 p.Arg688Gly](/variant/abcb6-p-arg688gly), [ABCB6 p.Arg688His](/variant/abcb6-p-arg688his), [ABCB6 p.Asn545Ser](/variant/abcb6-p-asn545ser).

### 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 4563834). 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.*