# NM_172245.4(CSF2RA):c.1116G>A (p.Val372=)

https://sugi.bio/variant/csf2ra-p-val372

## Summary

**CSF2RA p.Val372= (c.1116G>A)** is classified **Likely benign** in CSF2RA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-06). Very rare (popmax 0.00223%, eas); Associated with surfactant metabolism dysfunction, pulmonary, 4.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs754054970 · 2 submitters · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the CSF2RA gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to surfactant metabolism dysfunction, pulmonary, 4.

*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) |
| Diagnostic panels | CSF2RA is a diagnostic-grade gene on 5 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/0015263/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CSF2RA](https://sugi.bio/atlas/gene/CSF2RA/) |
| Protein change (HGVS p.) | p.Val372= |
| Coding change (HGVS c.) | c.1116G>A |
| MANE Select transcript | [NM_172245](https://www.ncbi.nlm.nih.gov/nuccore/NM_172245) |
| dbSNP | [rs754054970](https://www.ncbi.nlm.nih.gov/snp/rs754054970/) |
| Variant type | single nucleotide variant |
| Location | chrX:1305518-1305518 (GRCh38) |
| ClinVar | [VCV1114953](https://www.ncbi.nlm.nih.gov/clinvar/variation/1114953/) |

**All HGVS expressions:** `LRG_186:g.41719G>A`, `NC_000023.10:g.1424411G>A`, `NC_000023.11:g.1305518G>A`, `NC_000024.10:g.1305518G>A`, `NC_000024.9:g.1374411G>A`, `NG_012280.1:g.41719G>A`, `NM_001161529.2:c.1116G>A`, `NM_001161530.2:c.1218G>A`, `NM_001161531.2:c.1116G>A`, `NM_001161532.2:c.717G>A`, `NM_001379153.1:c.1218G>A`, `NM_001379154.1:c.1218G>A`, `NM_001379155.1:c.1116G>A`, `NM_001379156.1:c.1116G>A`, `NM_001379158.1:c.1116G>A`, `NM_001379159.1:c.1116G>A`, `NM_001379160.1:c.1086G>A`, `NM_001379161.1:c.1116G>A`, `NM_001379162.1:c.1116G>A`, `NM_001379163.1:c.1116G>A`, `NM_001379164.1:c.1116G>A`, `NM_001379165.1:c.1116G>A`, `NM_001379166.1:c.927G>A`, `NM_001379167.1:c.*17G>A`, `NM_001379168.1:c.*17G>A`, `NM_001379169.1:c.*17G>A`, `NM_006140.6:c.1116G>A`, `NM_172245.4:c.1116G>A`, `NM_172246.4:c.947-3884G>A`, `NM_172247.3:c.*17G>A`, `NM_172249.4:c.*17G>A`, `NR_027760.3:n.1160G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.39) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -11.309, GERP -0.288 — fast-evolving / accelerated position
- CADD: **PHRED 3.057**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.02**, acceptor gain **0.00**, donor gain **0.39**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.02**, acceptor gain **0.00**, donor gain **0.39**.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,882 in the highest group · 2/1,613,972 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,882 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,492 |

*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}

**CSF2RA** population constraint: ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **surfactant metabolism dysfunction, pulmonary, 4** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.15, 61% of residues very-high.

**2 experimental structure(s)** (PDB): [4NKQ](https://www.rcsb.org/structure/4NKQ), [4RS1](https://www.rcsb.org/structure/4RS1).

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

*Describes the biological roles of CSF2RA (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:** CSF2RA participates in disease-associated pathways. In Reactome, CSF2RA is annotated in disease pathway(s) including **Defective CSF2RA causes SMDP4**, **Defective CSF2RB causes SMDP5**.

**Disease mechanism (Reactome):** CSF2RA loss or alteration is curated in [Defective CSF2RA causes SMDP4](https://reactome.org/content/detail/R-HSA-5688890), [Defective CSF2RB causes SMDP5](https://reactome.org/content/detail/R-HSA-5688849).

### Pathways affected {#pathways}

CSF2RA participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective CSF2RA causes SMDP4](https://reactome.org/content/detail/R-HSA-5688890) | curated |
| ⚕ [Defective CSF2RB causes SMDP5](https://reactome.org/content/detail/R-HSA-5688849) | curated |
| [Interleukin receptor SHC signaling](https://reactome.org/content/detail/R-HSA-912526) | curated |
| [Interleukin-3, Interleukin-5 and GM-CSF signaling](https://reactome.org/content/detail/R-HSA-512988) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Surfactant metabolism](https://reactome.org/content/detail/R-HSA-5683826) | curated |

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

**Biological process:** cell surface receptor signaling pathway via JAK-STAT, granulocyte-macrophage colony-stimulating factor signaling pathway, positive regulation of leukocyte proliferation.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-06.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-06 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-08 |

## Associated conditions {#conditions}

[surfactant metabolism dysfunction, pulmonary, 4](https://sugi.bio/atlas/disease/surfactant-metabolism-dysfunction-pulmonary-4/).

**Reported phenotype names (ClinVar):** Surfactant metabolism dysfunction, pulmonary, 4, not specified, PAP DUE TO CSF2RA DEFICIENCY, PULMONARY ALVEOLAR PROTEINOSIS, CONGENITAL, 4, CSF2RA DEFICIENCY, AllHighlyPenetrant.

## Similar variants {#similar}

Related CSF2RA variant pages (same residue, condition, or type): [CSF2RA p.Arg199Ter](/variant/csf2ra-p-arg199ter), [CSF2RA p.Arg217Ter](/variant/csf2ra-p-arg217ter), [CSF2RA p.Gln204Ter](/variant/csf2ra-p-gln204ter), [CSF2RA p.Gln263Ter](/variant/csf2ra-p-gln263ter), [CSF2RA p.Arg354Gln](/variant/csf2ra-p-arg354gln), [CSF2RA p.Gly339Val](/variant/csf2ra-p-gly339val), [CSF2RA p.Gly386Arg](/variant/csf2ra-p-gly386arg), [CSF2RA p.Leu336Val](/variant/csf2ra-p-leu336val).

### 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 1114953). 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.*