# NM_001089.3(ABCA3):c.4711del (p.Ser1571fs)

https://sugi.bio/variant/abca3-p-ser1571fs

## Summary

**ABCA3 p.Ser1571fs (c.4711del)** is classified **Pathogenic** in ABCA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-20). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2505612312 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ABCA3 gene that is reported as disease-causing, but on limited review, 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 | [ABCA3](https://sugi.bio/atlas/gene/ABCA3/) |
| Protein change (HGVS p.) | p.Ser1571fs |
| Coding change (HGVS c.) | c.4711del |
| MANE Select transcript | [NM_001089](https://www.ncbi.nlm.nih.gov/nuccore/NM_001089) |
| dbSNP | [rs2505612312](https://www.ncbi.nlm.nih.gov/snp/rs2505612312/) |
| Variant type | Deletion |
| Location | chr16:2278295-2278295 (GRCh38) |
| ClinVar | [VCV2697616](https://www.ncbi.nlm.nih.gov/clinvar/variation/2697616/) |

**All HGVS expressions:** `NC_000016.10:g.2278295del`, `NC_000016.9:g.2328296del`, `NG_011790.1:g.67452del`, `NG_011790.2:g.67433del`, `NM_001089.3:c.4711del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.749, GERP 2.53, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.612, pLI 1.0831e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 30 of 33**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ABCA3** population constraint: LOEUF 0.612, pLI 1.0831e-10, missense-Z 1.3112. *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):

- **interstitial lung disease due to ABCA3 deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **1571** lies in the abc transporter 2 domain; a UniProt-annotated variant site (in smdp3).

AlphaFold model confidence (whole protein): pLDDT 81.00, 23% of residues very-high.

**2 experimental structure(s)** (PDB): [7W01](https://www.rcsb.org/structure/7W01), [7W02](https://www.rcsb.org/structure/7W02).

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

*Describes the biological roles of ABCA3 (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:** ABCA3's established molecular role includes ABC-type xenobiotic transporter activity. p.Ser1571fs falls in the abc transporter 2 domain. In Reactome, ABCA3 is annotated in disease pathway(s) including **Defective ABCA3 causes SMDP3**, **Defective ABCA3 causes SMDP3**.

**Disease mechanism (Reactome):** ABCA3 loss or alteration is curated in [Defective ABCA3 causes SMDP3](https://reactome.org/content/detail/R-HSA-5683678), [Defective ABCA3 causes SMDP3](https://reactome.org/content/detail/R-HSA-5688399).

### Pathways affected {#pathways}

ABCA3 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCA3 causes SMDP3](https://reactome.org/content/detail/R-HSA-5683678) | other |
| ⚕ [Defective ABCA3 causes SMDP3](https://reactome.org/content/detail/R-HSA-5688399) | other |
| [ABC transporters in lipid homeostasis](https://reactome.org/content/detail/R-HSA-1369062) | other |
| [Surfactant metabolism](https://reactome.org/content/detail/R-HSA-5683826) | other |

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

**Molecular function:** ABC-type xenobiotic transporter activity, ATP hydrolysis activity, phosphatidylcholine transfer activity, phosphatidylcholine flippase activity.

**Biological process:** xenobiotic transmembrane transport, positive regulation of cholesterol efflux, phospholipid transport, positive regulation of protein homooligomerization, xenobiotic transport, phosphatidylcholine metabolic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-20.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-20 |

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

## Similar variants {#similar}

Related ABCA3 variant pages (same residue, condition, or type): [ABCA3 p.Arg1333fs](/variant/abca3-p-arg1333fs), [ABCA3 p.Leu1584fs](/variant/abca3-p-leu1584fs), [ABCA3 p.Tyr273fs](/variant/abca3-p-tyr273fs), [ABCA3 p.Val1495fs](/variant/abca3-p-val1495fs), [ABCA3 c.1285+4_1285+7del](/variant/abca3-c-1285-plus-4-1285-plus-7del), [ABCA3 c.1467+1903_1612-126del](/variant/abca3-c-1467-plus-1903-1612-minus-126del), [ABCA3 p.Asp1058fs](/variant/abca3-p-asp1058fs), [ABCA3 p.Asp507fs](/variant/abca3-p-asp507fs).

### 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 2697616). 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.*