# NM_001089.3(ABCA3):c.998C>G (p.Pro333Arg)

https://sugi.bio/variant/abca3-p-pro333arg

## Summary

**ABCA3 p.Pro333Arg (c.998C>G)** is classified **Uncertain significance** in ABCA3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-03). AlphaMissense: likely benign (0.0722); Very rare (popmax 0.00203%, nfe); Associated with hereditary pulmonary alveolar proteinosis.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00203%, nfe)

## For patients & families {#patients}

This is a change in the ABCA3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to hereditary pulmonary alveolar proteinosis.

*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) | Adolescent, Adult, Childhood, Elderly, Infancy |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ABCA3 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Hereditary pulmonary alveolar proteinosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormal circulating protein level — Very frequent (99-80%)
- Failure to thrive in infancy — Frequent (79-30%)
- Restrictive ventilatory defect — Frequent (79-30%)
- Respiratory distress — Frequent (79-30%)
- Respiratory failure requiring assisted ventilation — Frequent (79-30%)
- Hypoxemia — Frequent (79-30%)
- Crazy paving pattern on pulmonary HRCT — Frequent (79-30%)
- Tachycardia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004582/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.Pro333Arg |
| Coding change (HGVS c.) | c.998C>G |
| MANE Select transcript | [NM_001089](https://www.ncbi.nlm.nih.gov/nuccore/NM_001089) |
| Variant type | single nucleotide variant |
| Location | chr16:2317396-2317396 (GRCh38) |
| ClinVar | [VCV3706727](https://www.ncbi.nlm.nih.gov/clinvar/variation/3706727/) |

**All HGVS expressions:** `NC_000016.10:g.2317396G>C`, `NC_000016.9:g.2367397G>C`, `NG_011790.1:g.28351C>G`, `NG_011790.2:g.28332C>G`, `NM_001089.2:c.998C>G`, `NM_001089.3:c.998C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0722)
- REVEL 0.214 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.727 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.92, GERP 0.22, phastCons 0.992 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 16.7**. 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 0.98** across the covering region of the MANE Select transcript (2,286,899–2,326,466), spanning 39,567 bp. Chi-square p 0.47. 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>A, Δ0.31 acceptor 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 **0.00203%** (nfe) · FAF95 0.00138% · FAF99 0.00116% · 24/1,180,012 in the highest group · 25/1,613,642 alleles overall — very rare (popmax 0.00203%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00203% | 49,167 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |

*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}


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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-03.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-08 |

## Associated conditions {#conditions}

[hereditary pulmonary alveolar proteinosis](https://sugi.bio/atlas/disease/hereditary-pulmonary-alveolar-proteinosis/).

**Reported phenotype names (ClinVar):** Hereditary pulmonary alveolar proteinosis, not provided, Pulmonary surfactant metabolism dysfunction, none provided.

## Similar variants {#similar}

Related ABCA3 variant pages (same residue, condition, or type): [ABCA3 c.2053-1G>C](/variant/abca3-c-2053-minus-1g-c), [ABCA3 c.3863-98C>T](/variant/abca3-c-3863-minus-98c-t), [ABCA3 p.Arg1550Trp](/variant/abca3-p-arg1550trp), [ABCA3 p.Arg43Cys](/variant/abca3-p-arg43cys), [ABCA3 p.Arg43His](/variant/abca3-p-arg43his), [ABCA3 p.Glu1540Lys](/variant/abca3-p-glu1540lys), [ABCA3 p.Glu292Val](/variant/abca3-p-glu292val), [ABCA3 p.Gly1459Asp](/variant/abca3-p-gly1459asp).

### 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 3706727). 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.*