# NM_000395.3(CSF2RB):c.87G>A (p.Pro29=)

https://sugi.bio/variant/csf2rb-p-pro29

## Summary

**CSF2RB p.Pro29= (c.87G>A)** is classified **Likely benign** in CSF2RB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-30). Ultra-rare (popmax 0.0131%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs372145171 · 1 submitter · ultra-rare (popmax 0.0131%, nfe)

## For patients & families {#patients}

This is a change in the CSF2RB 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 | [CSF2RB](https://sugi.bio/atlas/gene/CSF2RB/) |
| Protein change (HGVS p.) | p.Pro29= |
| Coding change (HGVS c.) | c.87G>A |
| MANE Select transcript | [NM_000395](https://www.ncbi.nlm.nih.gov/nuccore/NM_000395) |
| dbSNP | [rs372145171](https://www.ncbi.nlm.nih.gov/snp/rs372145171/) |
| Variant type | single nucleotide variant |
| Location | chr22:36923254-36923254 (GRCh38) |
| ClinVar | [VCV1901109](https://www.ncbi.nlm.nih.gov/clinvar/variation/1901109/) |

**All HGVS expressions:** `NC_000022.10:g.37319296G>A`, `NC_000022.11:g.36923254G>A`, `NG_008040.1:g.14622G>A`, `NM_000395.3:c.87G>A`, `NM_001410827.1:c.87G>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 (below), not from a missing predictor score.
- Conservation: phyloP -14.109, GERP -2.73 — fast-evolving / accelerated position
- CADD: **PHRED 0.548**. 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 (G>T, Δ0.38 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 **0.0131%** (nfe) · FAF95 0.0114% · FAF99 0.0107% · 155/1,180,022 in the highest group · 163/1,614,048 alleles overall — ultra-rare (popmax 0.0131%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 0.11% | 910 |
| European (non-Finnish) (grpmax) | 0.0131% | 7,613 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,827 |
| African / African-American | 0.004% | 24,973 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,042 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CSF2RB** population constraint: LOEUF 0.511, pLI 0.9326, missense-Z 0.88803; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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, 5** — Definitive (AR)

## Protein context {#protein}

Residue **29** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 65.50, 38% of residues very-high.

**10 experimental structure(s)** (PDB): [1C8P](https://www.rcsb.org/structure/1C8P), [1EGJ](https://www.rcsb.org/structure/1EGJ), [1GH7](https://www.rcsb.org/structure/1GH7), [2GYS](https://www.rcsb.org/structure/2GYS), [2NA8](https://www.rcsb.org/structure/2NA8), [2NA9](https://www.rcsb.org/structure/2NA9) — incl. mutant structure 2NA9.

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

*Describes the biological roles of CSF2RB (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:** CSF2RB's established molecular role includes coreceptor activity. In Reactome, CSF2RB is annotated in disease pathway(s) including **Defective CSF2RA causes SMDP4**, **Defective CSF2RB causes SMDP5**.

**Disease mechanism (Reactome):** CSF2RB 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}

CSF2RB 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 |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Surfactant metabolism](https://reactome.org/content/detail/R-HSA-5683826) | curated |
| [Interleukin-3, Interleukin-5 and GM-CSF signaling](https://reactome.org/content/detail/R-HSA-512988) | electronic |

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

**Molecular function:** coreceptor activity.

**Biological process:** cell surface receptor signaling pathway via JAK-STAT, interleukin-5-mediated signaling pathway, interleukin-3-mediated signaling pathway, granulocyte-macrophage colony-stimulating factor signaling pathway, positive regulation of leukocyte proliferation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-30.

**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 | 2025-05-30 |

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

## Similar variants {#similar}

Related CSF2RB variant pages (same residue, condition, or type): [CSF2RB p.Pro29Leu](/variant/csf2rb-p-pro29leu), [CSF2RB p.Ala185Thr](/variant/csf2rb-p-ala185thr), [CSF2RB p.Ala255Thr](/variant/csf2rb-p-ala255thr), [CSF2RB p.Ala314Thr](/variant/csf2rb-p-ala314thr), [CSF2RB p.Ala314Val](/variant/csf2rb-p-ala314val), [CSF2RB p.Ala394Thr](/variant/csf2rb-p-ala394thr), [CSF2RB p.Ala455Thr](/variant/csf2rb-p-ala455thr), [CSF2RB p.Ala576Thr](/variant/csf2rb-p-ala576thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 1901109). 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.*