# NM_172219.3(CSF3):c.338T>G (p.Phe113Cys)

https://sugi.bio/variant/csf3-p-phe113cys

## Summary

**CSF3 p.Phe113Cys (c.338T>G)** is classified **Uncertain significance** in CSF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: likely benign (0.2519); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2544043938 · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CSF3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [CSF3](https://sugi.bio/atlas/gene/CSF3/) |
| Protein change (HGVS p.) | p.Phe113Cys |
| Coding change (HGVS c.) | c.338T>G |
| MANE Select transcript | [NM_172219](https://www.ncbi.nlm.nih.gov/nuccore/NM_172219) |
| dbSNP | [rs2544043938](https://www.ncbi.nlm.nih.gov/snp/rs2544043938/) |
| Variant type | single nucleotide variant |
| Location | chr17:40016519-40016519 (GRCh38) |
| ClinVar | [VCV3078002](https://www.ncbi.nlm.nih.gov/clinvar/variation/3078002/) |

**All HGVS expressions:** `NC_000017.10:g.38172772T>G`, `NC_000017.11:g.40016519T>G`, `NM_000759.4:c.347T>G`, `NM_001178147.2:c.230T>G`, `NM_172219.3:c.338T>G`, `NM_172220.3:c.239T>G`, `NR_033662.2:n.549T>G`, `NR_168489.1:n.441T>G`, `NR_168490.1:n.450T>G`, `NR_168491.1:n.558T>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** (0.2519)
- REVEL 0.02 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.944 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.45) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.053, GERP 1.29, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **F116C** vs ClinVar **F113C**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 19.17**. 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 0.82** across the covering region of the MANE Select transcript (40,015,475–40,016,956), spanning 1,481 bp. Chi-square p 0.0041. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.45**, donor loss **0.00**, acceptor gain **0.05**, donor gain **0.00**. Largest is acceptor loss, 11 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.05**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**CSF3** population constraint: LOEUF 1.237, pLI 4.9096e-06, missense-Z 0.93431. *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 **113** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 84.67, 56% of residues very-high.

**7 experimental structure(s)** (PDB): [1CD9](https://www.rcsb.org/structure/1CD9), [1GNC](https://www.rcsb.org/structure/1GNC), [1PGR](https://www.rcsb.org/structure/1PGR), [1RHG](https://www.rcsb.org/structure/1RHG), [2D9Q](https://www.rcsb.org/structure/2D9Q), [5GW9](https://www.rcsb.org/structure/5GW9).

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

*Describes the biological roles of CSF3 (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:** CSF3's established molecular role includes cytokine activity.


### Pathways affected {#pathways}

CSF3 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Differentiation of Circulating Monocytes](https://reactome.org/content/detail/R-HSA-9968734) | curated |
| [Interleukin-10 signaling](https://reactome.org/content/detail/R-HSA-6783783) | curated |
| [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 |

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

**Molecular function:** cytokine activity, enzyme binding.

**Biological process:** positive regulation of actin filament polymerization, granulocyte colony-stimulating factor signaling pathway, positive regulation of transcription by RNA polymerase II, positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction, cellular response to cytokine stimulus, regulation of actin filament organization.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-27.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-27 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CSF3 variant pages (same residue, condition, or type): [CSF3 p.Ala171Thr](/variant/csf3-p-ala171thr), [CSF3 p.Leu154Met](/variant/csf3-p-leu154met), [CSF3 p.Pro168=](/variant/csf3-p-pro168), [CSF3 p.Ala23Thr](/variant/csf3-p-ala23thr), [CSF3 p.Ala59Thr](/variant/csf3-p-ala59thr), [CSF3 p.Ala5Val](/variant/csf3-p-ala5val), [CSF3 p.Glu123Val](/variant/csf3-p-glu123val), [CSF3 p.His73Gln](/variant/csf3-p-his73gln).

### 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 3078002). 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.*