# NM_001288705.3(CSF1R):c.705C>A (p.Val235=)

https://sugi.bio/variant/csf1r-p-val235

## Summary

**CSF1R p.Val235= (c.705C>A)** is classified **Likely benign** in CSF1R (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-15). Very rare (popmax 0.00167%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs2481039115 · 1 submitter · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the CSF1R 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 | [CSF1R](https://sugi.bio/atlas/gene/CSF1R/) |
| Protein change (HGVS p.) | p.Val235= |
| Coding change (HGVS c.) | c.705C>A |
| MANE Select transcript | [NM_001288705](https://www.ncbi.nlm.nih.gov/nuccore/NM_001288705) |
| dbSNP | [rs2481039115](https://www.ncbi.nlm.nih.gov/snp/rs2481039115/) |
| Variant type | single nucleotide variant |
| Location | chr5:150078136-150078136 (GRCh38) |
| ClinVar | [VCV1956334](https://www.ncbi.nlm.nih.gov/clinvar/variation/1956334/) |

**All HGVS expressions:** `NC_000005.10:g.150078136G>T`, `NC_000005.9:g.149457699G>T`, `NG_012303.2:g.40237C>A`, `NG_055557.1:g.242G>T`, `NM_001288705.3:c.705C>A`, `NM_001349736.2:c.705C>A`, `NM_001375320.1:c.705C>A`, `NM_001375321.1:c.261C>A`, `NM_005211.4:c.705C>A`, `NR_109969.2:n.832C>A`, `NR_164679.1:n.761C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.743, GERP 0.811, phastCons 0.994 — highly conserved position (PP3-type support)
- CADD: **PHRED 4.853**. 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 deltas (raw): acceptor loss **0.01**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 24 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, 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 (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/60,016 in the highest group · 1/1,461,858 alleles overall — very rare (popmax 0.00167%, amr).

*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 **235** lies in a β-strand; a disulfide bond; the ig-like c2-type 3 domain.

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.Val235= falls in the ig-like c2-type 3 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-15.

**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 | 2024-01-15 |

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

## Similar variants {#similar}

Related CSF1R variant pages (same residue, condition, or type): [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.Arg782Cys](/variant/csf1r-p-arg782cys), [CSF1R p.Arg782His](/variant/csf1r-p-arg782his), [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 1956334). 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.*