# NM_005689.4(ABCB6):c.171T>C (p.Ala57=)

https://sugi.bio/variant/abcb6-p-ala57

## Summary

**ABCB6 p.Ala57= (c.171T>C)** is classified **Likely benign** in ABCB6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-20). Very rare (popmax 0.00297%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs771029888 · 1 submitter · very rare (popmax 0.00297%, nfe)

## For patients & families {#patients}

This is a change in the ABCB6 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.Ala57= |
| Coding change (HGVS c.) | c.171T>C |
| MANE Select transcript | [NM_005689](https://www.ncbi.nlm.nih.gov/nuccore/NM_005689) |
| dbSNP | [rs771029888](https://www.ncbi.nlm.nih.gov/snp/rs771029888/) |
| Variant type | single nucleotide variant |
| Location | chr2:219218503-219218503 (GRCh38) |
| ClinVar | [VCV1619088](https://www.ncbi.nlm.nih.gov/clinvar/variation/1619088/) |

**All HGVS expressions:** `LRG_824:g.5488T>C`, `LRG_824t1:c.171T>C`, `NC_000002.11:g.220083225A>G`, `NC_000002.12:g.219218503A>G`, `NG_032110.1:g.5488T>C`, `NM_001349828.2:c.171T>C`, `NM_005689.4:c.171T>C`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -2.111, GERP -4.41 — fast-evolving / accelerated position
- CADD: **PHRED 0.461**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.60 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 (gnomAD v4.1): grpmax **0.00297%** (nfe) · FAF95 0.00216% · FAF99 0.00191% · 35/1,178,452 in the highest group · 36/1,609,258 alleles overall — very rare (popmax 0.00297%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00297% | 33,670 |
| African / African-American | 0.00134% | 74,898 |

*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 **57** lies in the 'required for atpase activity' region; the 'required for the lysosomal targeting' region; a UniProt-annotated variant site (in mcopcb7; uncertain significance; hypomorphic mutation).

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.Ala57= 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-20.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-20 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ABCB6 variant pages (same residue, condition, or type): [ABCB6 p.Ala57Thr](/variant/abcb6-p-ala57thr), [ABCB6 p.Ala164Thr](/variant/abcb6-p-ala164thr), [ABCB6 p.Ala66Thr](/variant/abcb6-p-ala66thr), [ABCB6 p.Ala681Thr](/variant/abcb6-p-ala681thr), [ABCB6 p.Arg135Ser](/variant/abcb6-p-arg135ser), [ABCB6 p.Arg439Cys](/variant/abcb6-p-arg439cys), [ABCB6 p.Arg450Gln](/variant/abcb6-p-arg450gln), [ABCB6 p.Arg685His](/variant/abcb6-p-arg685his).

### 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 1619088). 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.*