# NM_001288705.3(CSF1R):c.2345G>A (p.Arg782His)

https://sugi.bio/variant/csf1r-p-arg782his

## Summary

**CSF1R p.Arg782His (c.2345G>A)** is classified **Pathogenic/Likely pathogenic** in CSF1R (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-04-22). AlphaMissense: likely pathogenic (0.9927); Absent from gnomAD v4.1; Associated with brain abnormalities, neurodegeneration, and dysosteosclerosis.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs281860281 · 6 submitters · 4 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CSF1R gene that is considered likely disease-causing, submitted by 6 submitters, and is linked to brain abnormalities, neurodegeneration, and dysosteosclerosis.

*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 | [CSF1R](https://sugi.bio/atlas/gene/CSF1R/) |
| Protein change (HGVS p.) | p.Arg782His |
| Coding change (HGVS c.) | c.2345G>A |
| MANE Select transcript | [NM_001288705](https://www.ncbi.nlm.nih.gov/nuccore/NM_001288705) |
| dbSNP | [rs281860281](https://www.ncbi.nlm.nih.gov/snp/rs281860281/) |
| Variant type | single nucleotide variant |
| Location | chr5:150056316-150056316 (GRCh38) |
| ClinVar | [VCV38378](https://www.ncbi.nlm.nih.gov/clinvar/variation/38378/) |

**All HGVS expressions:** `NC_000005.10:g.150056316C>T`, `NC_000005.9:g.149435879C>T`, `NG_012303.2:g.62057G>A`, `NM_001288705.3:c.2345G>A`, `NM_001349736.2:c.2345G>A`, `NM_001375320.1:c.2345G>A`, `NM_001375321.1:c.1901G>A`, `NM_005211.4:c.2345G>A`, `NR_109969.2:n.2309G>A`, `NR_164679.1:n.2238G>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9927) — concordant with the pathogenic call
- REVEL 0.869 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.904 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.681, GERP 2, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in CSF1R (of 5,727 modeled).
- CADD: **PHRED 27.9**. 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 0.39** across the covering region of the MANE Select transcript (150,054,352–150,057,304), spanning 2,952 bp. Chi-square p 1.2e-16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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}

**CSF1R** population constraint: LOEUF 0.485, pLI 0.97537, missense-Z 2.4273. *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):

- **brain abnormalities, neurodegeneration, and dysosteosclerosis** — Definitive (AR)
- **leukoencephalopathy, diffuse hereditary, with spheroids 1** — Definitive (AD)

## Protein context {#protein}

Residue **782** lies in the protein kinase domain; an α-helix; a UniProt-annotated variant site (in banddos); a UniProt-annotated variant site (in hdls1); a UniProt-annotated variant site (in hdls1; impairs autophosphorylation upon stimulation with csf1).

AlphaFold model confidence (whole protein): pLDDT 78.08, 47% of residues very-high.

**26 experimental structure(s)** (PDB): [2I0V](https://www.rcsb.org/structure/2I0V), [2I0Y](https://www.rcsb.org/structure/2I0Y), [2I1M](https://www.rcsb.org/structure/2I1M), [2OGV](https://www.rcsb.org/structure/2OGV), [3BEA](https://www.rcsb.org/structure/3BEA), [3DPK](https://www.rcsb.org/structure/3DPK).

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

*Describes the biological roles of CSF1R (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:** CSF1R's established molecular role includes macrophage colony-stimulating factor receptor activity. p.Arg782His falls in the protein kinase domain.


### Pathways affected {#pathways}

CSF1R participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Other interleukin signaling](https://reactome.org/content/detail/R-HSA-449836) | curated |
| [Transcriptional Regulation by VENTX](https://reactome.org/content/detail/R-HSA-8853884) | 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:** macrophage colony-stimulating factor receptor activity, cytokine binding.

**Biological process:** positive regulation of protein phosphorylation, cell population proliferation, positive regulation of cell population proliferation, regulation of cell shape, positive regulation of macrophage chemotaxis, peptidyl-tyrosine phosphorylation.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-22.

**Submitter consensus:** conflicting (5 Pathogenic, 1 Likely pathogenic).

**Submission history:** 6 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-13 |
| Illumina Laboratory Services, Illumina | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-09-04 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-08-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-10-22 |
| Clinical Genetics Laboratory, Skane University Hospital Lund | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-22 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2013-03-12 |

## Associated conditions {#conditions}

[brain abnormalities, neurodegeneration, and dysosteosclerosis](https://sugi.bio/atlas/disease/brain-abnormalities-neurodegeneration-and-dysosteosclerosis/), [neurodegenerative disease](https://sugi.bio/atlas/disease/neurodegenerative-disease/), [leukoencephalopathy, hereditary diffuse, with spheroids](https://sugi.bio/atlas/disease/leukoencephalopathy-hereditary-diffuse-with-spheroids/), [leukoencephalopathy, diffuse hereditary, with spheroids 1](https://sugi.bio/atlas/disease/leukoencephalopathy-diffuse-hereditary-with-spheroids-1/).

**Reported phenotype names (ClinVar):** Brain abnormalities, neurodegeneration, and dysosteosclerosis, Hereditary diffuse leukoencephalopathy with spheroids, not provided, Leukoencephalopathy, diffuse hereditary, with spheroids 1, Neurodegeneration, DEMENTIA, FAMILIAL, NEUMANN TYPE, SUBCORTICAL GLIOSIS OF NEUMANN, CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, none provided, Neurodegenerative disease.

## Same-residue context {#hotspot}

Residue **782** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [CSF1R p.Arg782Cys](/variant/csf1r-p-arg782cys), [CSF1R p.Arg782Leu](/variant/csf1r-p-arg782leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CSF1R variant pages (same residue, condition, or type): [CSF1R p.Arg782Cys](/variant/csf1r-p-arg782cys), [CSF1R p.Arg782Leu](/variant/csf1r-p-arg782leu), [CSF1R p.Ala780Val](/variant/csf1r-p-ala780val), [CSF1R p.Ala781Val](/variant/csf1r-p-ala781val), [CSF1R p.Arg676Ter](/variant/csf1r-p-arg676ter), [CSF1R p.Arg777Gln](/variant/csf1r-p-arg777gln), [CSF1R p.Arg777Trp](/variant/csf1r-p-arg777trp), [CSF1R p.Gln481Ter](/variant/csf1r-p-gln481ter).

### 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 38378). 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.*