# NM_000760.4(CSF3R):c.137_138delinsTT (p.Cys46Phe)

https://sugi.bio/variant/csf3r-p-cys46phe

## Summary

**CSF3R p.Cys46Phe (c.137_138delinsTT)** is classified **Uncertain significance** in CSF3R (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). No gnomAD frequency available for this variant; Associated with autosomal recessive severe congenital neutropenia due to CSF3R deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2521830774 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CSF3R gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to autosomal recessive severe congenital neutropenia due to CSF3R deficiency.

*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) | Infancy, Neonatal |
| Diagnostic panels | CSF3R is a diagnostic-grade gene on 5 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017698/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CSF3R](https://sugi.bio/atlas/gene/CSF3R/) |
| Protein change (HGVS p.) | p.Cys46Phe |
| Coding change (HGVS c.) | c.137_138delinsTT |
| MANE Select transcript | [NM_000760](https://www.ncbi.nlm.nih.gov/nuccore/NM_000760) |
| dbSNP | [rs2521830774](https://www.ncbi.nlm.nih.gov/snp/rs2521830774/) |
| Variant type | Indel |
| Location | chr1:36475600-36475601 (GRCh38) |
| ClinVar | [VCV2794048](https://www.ncbi.nlm.nih.gov/clinvar/variation/2794048/) |

**All HGVS expressions:** `LRG_144:g.12308_12309delinsTT`, `LRG_144t1:c.137_138delinsTT`, `LRG_144t2:c.137_138delinsTT`, `NC_000001.10:g.36941201_36941202delinsAA`, `NC_000001.11:g.36475600_36475601delinsAA`, `NG_016270.1:g.12308_12309delinsTT`, `NM_000760.4:c.137_138delinsTT`, `NM_156039.3:c.137_138delinsTT`, `NM_172313.3:c.137_138delinsTT`

## 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 1.43, GERP -1.73, phastCons 0.833 — weakly conserved position
- Regional missense constraint: **o/e 0.84** across the covering region of the MANE Select transcript (36,466,360–36,479,496), spanning 13,136 bp. Chi-square p 3.4e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel 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}

**CSF3R** population constraint: LOEUF 0.726, pLI 3.6121e-09, missense-Z 2.4079. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **46** lies in a disulfide bond; a β-strand; the ig-like c2-type domain.

AlphaFold model confidence (whole protein): pLDDT 74.29, 37% of residues very-high.

**1 experimental structure(s)** (PDB): [2D9Q](https://www.rcsb.org/structure/2D9Q).

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

*Describes the biological roles of CSF3R (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.*


### Pathways affected {#pathways}

CSF3R participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Other interleukin signaling](https://reactome.org/content/detail/R-HSA-449836) | curated |
| [Inactivation of CSF3 (G-CSF) signaling](https://reactome.org/content/detail/R-HSA-9705462) | electronic |
| [Signaling by CSF3 (G-CSF)](https://reactome.org/content/detail/R-HSA-9674555) | electronic |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | electronic |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-07.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-07 |

## Associated conditions {#conditions}

[autosomal recessive severe congenital neutropenia due to CSF3R deficiency](https://sugi.bio/atlas/disease/autosomal-recessive-severe-congenital-neutropenia-due-to-csf3r-deficiency/).

**Reported phenotype names (ClinVar):** Autosomal recessive severe congenital neutropenia due to CSF3R deficiency, Neutropenia, severe congenital, 7, autosomal recessive.

## Similar variants {#similar}

Related CSF3R variant pages (same residue, condition, or type): [CSF3R p.Ser471Lys](/variant/csf3r-p-ser471lys), [CSF3R p.Pro215_Leu217delinsTer](/variant/csf3r-p-pro215-leu217delinster), [CSF3R p.Ala520Asn](/variant/csf3r-p-ala520asn), [CSF3R p.Ala832Lys](/variant/csf3r-p-ala832lys), [CSF3R p.Glu450Met](/variant/csf3r-p-glu450met), [CSF3R c.1072-1G>A](/variant/csf3r-c-1072-minus-1g-a), [CSF3R c.843+2T>C](/variant/csf3r-c-843-plus-2t-c), [CSF3R c.998-2A>T](/variant/csf3r-c-998-minus-2a-t).

### 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 2794048). 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.*