# NM_001089.3(ABCA3):c.3145T>C (p.Ser1049Pro)

https://sugi.bio/variant/abca3-p-ser1049pro

## Summary

**ABCA3 p.Ser1049Pro (c.3145T>C)** is classified **Likely pathogenic** in ABCA3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-05). AlphaMissense: likely pathogenic (0.9469); Very rare (popmax 8.47e-05%, nfe); Associated with carbamoyl phosphate synthetase I deficiency disease.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs1460001890 · 4 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the ABCA3 gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to carbamoyl phosphate synthetase I deficiency disease.

*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 |
| Age of onset (of this condition) | All ages |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ABCA3 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Carbamoyl-phosphate synthetase 1 deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Seizure — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Episodic ammonia intoxication — Very frequent (99-80%)
- Hyperammonemia — Very frequent (99-80%)
- Respiratory insufficiency — Very frequent (99-80%)
- Aminoaciduria — Very frequent (99-80%)
- Hypoargininemia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007269/index) · [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.Ser1049Pro |
| Coding change (HGVS c.) | c.3145T>C |
| MANE Select transcript | [NM_001089](https://www.ncbi.nlm.nih.gov/nuccore/NM_001089) |
| dbSNP | [rs1460001890](https://www.ncbi.nlm.nih.gov/snp/rs1460001890/) |
| Variant type | single nucleotide variant |
| Location | chr16:2286827-2286827 (GRCh38) |
| ClinVar | [VCV1504022](https://www.ncbi.nlm.nih.gov/clinvar/variation/1504022/) |

**All HGVS expressions:** `NC_000016.10:g.2286827A>G`, `NC_000016.9:g.2336828A>G`, `NG_011790.1:g.58920T>C`, `NM_001089.2:c.3145T>C`, `NM_001089.3:c.3145T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9469) — concordant with the pathogenic call
- REVEL 0.735 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.041 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.369, GERP 2.53, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in ABCA3 (of 10,012 modeled).
- CADD: **PHRED 25.4**. 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 0.53** across the covering region of the MANE Select transcript (2,286,795–2,286,898), spanning 103 bp. Chi-square p 0.00085. 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 **8.47e-05%** (nfe) · 1/1,180,000 in the highest group · 1/1,461,818 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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 **1049** lies in an α-helix.

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. 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}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-05.

**Submitter consensus:** unanimous (5/5 Likely pathogenic).

**Submission history:** 5 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-11-08 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-12-17 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-09-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-04-02 |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-11-05 |

## Associated conditions {#conditions}

[carbamoyl phosphate synthetase I deficiency disease](https://sugi.bio/atlas/disease/carbamoyl-phosphate-synthetase-i-deficiency-disease/), [interstitial lung disease due to ABCA3 deficiency](https://sugi.bio/atlas/disease/interstitial-lung-disease-due-to-abca3-deficiency/).

**Reported phenotype names (ClinVar):** Congenital hyperammonemia, type I, not provided, Interstitial lung disease due to ABCA3 deficiency, Carbamoyl phosphate synthetase 1 deficiency, Hyperammonemia due to carbamoyl phosphate synthetase 1 deficiency, CPS 1 deficiency, Carbamyl phosphate synthetase (CPS) deficiency, CPS I DEFICIENCY, Carbamoyl-phosphate synthase I deficiency, Carbamoyl phosphate synthetase I deficiency disease.

## Similar variants {#similar}

Related ABCA3 variant pages (same residue, condition, or type): [ABCA3 c.1112-20G>A](/variant/abca3-c-1112-minus-20g-a), [ABCA3 c.2414+1G>A](/variant/abca3-c-2414-plus-1g-a), [ABCA3 c.3863-98C>T](/variant/abca3-c-3863-minus-98c-t), [ABCA3 c.614-2A>G](/variant/abca3-c-614-minus-2a-g), [ABCA3 p.Ala1070Thr](/variant/abca3-p-ala1070thr), [ABCA3 p.Arg1550Trp](/variant/abca3-p-arg1550trp), [ABCA3 p.Arg155Trp](/variant/abca3-p-arg155trp), [ABCA3 p.Arg208Trp](/variant/abca3-p-arg208trp).

### 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 1504022). 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.*