# NM_000757.6(CSF1):c.43T>A (p.Trp15Arg)

https://sugi.bio/variant/csf1-p-trp15arg

## Summary

**CSF1 p.Trp15Arg (c.43T>A)** is classified **Uncertain significance** in CSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.7203); Very rare (popmax 0.00452%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00452%, sas)

## For patients & families {#patients}

This is a change in the CSF1 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 | [CSF1](https://sugi.bio/atlas/gene/CSF1/) |
| Protein change (HGVS p.) | p.Trp15Arg |
| Coding change (HGVS c.) | c.43T>A |
| MANE Select transcript | [NM_000757](https://www.ncbi.nlm.nih.gov/nuccore/NM_000757) |
| Variant type | single nucleotide variant |
| Location | chr1:109914262-109914262 (GRCh38) |
| ClinVar | [VCV4234798](https://www.ncbi.nlm.nih.gov/clinvar/variation/4234798/) |

**All HGVS expressions:** `NC_000001.10:g.110456884T>A`, `NC_000001.11:g.109914262T>A`, `NG_030008.1:g.8652T>A`, `NG_030008.2:g.8758T>A`, `NM_000757.6:c.43T>A`, `NM_172210.3:c.43T>A`, `NM_172211.4:c.43T>A`, `NM_172212.3:c.43T>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.7203)
- REVEL 0.263 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -5.78 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 7.927, GERP 1.73, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in CSF1 (of 3,254 modeled).
- CADD: **PHRED 26.9**. 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 1.17** across the covering region of the MANE Select transcript (109,911,024–109,914,327), spanning 3,303 bp. Chi-square p 0.27. 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 (T>G, Δ0.73 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 **0.00452%** (sas) · FAF95 0.00145% · FAF99 0.000911% · 4/88,476 in the highest group · 5/1,603,564 alleles overall — very rare (popmax 0.00452%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00452% | 22,119 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,186 |

*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}

**CSF1** population constraint: LOEUF 0.338, pLI 0.99999, missense-Z 0.49258. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 58.62, 26% of residues very-high.

**8 experimental structure(s)** (PDB): [1HMC](https://www.rcsb.org/structure/1HMC), [3UEZ](https://www.rcsb.org/structure/3UEZ), [3UF2](https://www.rcsb.org/structure/3UF2), [4ADF](https://www.rcsb.org/structure/4ADF), [4FA8](https://www.rcsb.org/structure/4FA8), [4WRL](https://www.rcsb.org/structure/4WRL) — incl. mutant structure 5LXF.

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

*Describes the biological roles of CSF1 (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:** CSF1's established molecular role includes cytokine activity.


### Pathways affected {#pathways}

CSF1 participates in **7 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 |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | curated |
| [Signaling by CSF1 (M-CSF) in myeloid cells](https://reactome.org/content/detail/R-HSA-9680350) | electronic |

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

**Molecular function:** cytokine activity, growth factor activity, identical protein binding, protein homodimerization activity.

**Biological process:** response to ischemia, cell surface receptor protein tyrosine kinase signaling pathway, positive regulation of cell population proliferation, positive regulation of gene expression, positive regulation of macrophage derived foam cell differentiation, positive regulation of macrophage chemotaxis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-15.

**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 | 2025-07-15 |

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

## Similar variants {#similar}

Related CSF1 variant pages (same residue, condition, or type): [CSF1 p.Ala511=](/variant/csf1-p-ala511), [CSF1 p.Glu292=](/variant/csf1-p-glu292), [CSF1 p.Ala286Asp](/variant/csf1-p-ala286asp), [CSF1 p.Ala3Thr](/variant/csf1-p-ala3thr), [CSF1 p.Ala460Glu](/variant/csf1-p-ala460glu), [CSF1 p.Arg252Trp](/variant/csf1-p-arg252trp), [CSF1 p.Arg374Met](/variant/csf1-p-arg374met), [CSF1 p.Arg449Gln](/variant/csf1-p-arg449gln).

### 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 4234798). 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.*