# NM_002880.4(RAF1):c.699T>C (p.Ser233=)

https://sugi.bio/variant/raf1-p-ser233

## Summary

**RAF1 p.Ser233= (c.699T>C)** is classified **Likely benign** in RAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-19). Ultra-rare (popmax 0.0154%, sas); Associated with Cardiovascular phenotype.

**At a glance:** Likely benign · review: Single submitter · rsID rs750634045 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0154%, sas)

## For patients & families {#patients}

This is a change in the RAF1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Cardiovascular phenotype.

*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 | [RAF1](https://sugi.bio/atlas/gene/RAF1/) |
| Protein change (HGVS p.) | p.Ser233= |
| Coding change (HGVS c.) | c.699T>C |
| MANE Select transcript | [NM_002880](https://www.ncbi.nlm.nih.gov/nuccore/NM_002880) |
| dbSNP | [rs750634045](https://www.ncbi.nlm.nih.gov/snp/rs750634045/) |
| Variant type | single nucleotide variant |
| Location | chr3:12604271-12604271 (GRCh38) |
| ClinVar | [VCV1756538](https://www.ncbi.nlm.nih.gov/clinvar/variation/1756538/) |

**All HGVS expressions:** `LRG_413:g.64909T>C`, `LRG_413t1:c.699T>C`, `LRG_413t2:c.699T>C`, `NC_000003.11:g.12645770A>G`, `NC_000003.12:g.12604271A>G`, `NG_007467.1:g.64909T>C`, `NM_001354689.3:c.699T>C`, `NM_001354690.3:c.699T>C`, `NM_001354691.3:c.456T>C`, `NM_001354692.3:c.456T>C`, `NM_001354693.3:c.600T>C`, `NM_001354694.3:c.456T>C`, `NM_001354695.3:c.357T>C`, `NM_002880.4:c.699T>C`, `NR_148940.3:n.1030T>C`, `NR_148941.3:n.1030T>C`, `NR_148942.3:n.1030T>C`

## 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 3.743, GERP -0.274, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 12.82**. 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: **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 (gnomAD v4.1): grpmax **0.0154%** (sas) · FAF95 0.0092% · FAF99 0.00735% · 14/91,078 in the highest group · 14/1,461,836 alleles overall — ultra-rare (popmax 0.0154%, sas).

*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}

**RAF1** population constraint: LOEUF 0.353, pLI 1, missense-Z 3.4281. *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):

- **Costello syndrome** — Disputed (AD)
- **Noonan syndrome** — Definitive (AD)
- **cardiofaciocutaneous syndrome** — Disputed (AD)
- **Noonan syndrome with multiple lentigines** — Limited (AD)

## Protein context {#protein}

Residue **233** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 68.24, 30% of residues very-high.

**76 experimental structure(s)** (PDB): [1C1Y](https://www.rcsb.org/structure/1C1Y), [1FAQ](https://www.rcsb.org/structure/1FAQ), [1FAR](https://www.rcsb.org/structure/1FAR), [1GUA](https://www.rcsb.org/structure/1GUA), [1RFA](https://www.rcsb.org/structure/1RFA), [3CU8](https://www.rcsb.org/structure/3CU8) — incl. mutant structure 1GUA.

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

*Describes the biological roles of RAF1 (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:** RAF1's established molecular role includes protein kinase activity. p.Ser233= falls in the disordered region. In Reactome, RAF1 is annotated in disease pathway(s) including **Gain-of-function MRAS complexes activate RAF signaling**, **Paradoxical activation of RAF signaling by kinase inactive BRAF**.

**Disease mechanism (Reactome):** RAF1 loss or alteration is curated in [Gain-of-function MRAS complexes activate RAF signaling](https://reactome.org/content/detail/R-HSA-9726842), [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [SHOC2 M1731 mutant abolishes MRAS complex function](https://reactome.org/content/detail/R-HSA-9726840).

### Pathways affected {#pathways}

RAF1 participates in **17 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Gain-of-function MRAS complexes activate RAF signaling](https://reactome.org/content/detail/R-HSA-9726842) | curated |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [SHOC2 M1731 mutant abolishes MRAS complex function](https://reactome.org/content/detail/R-HSA-9726840) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| [CD209 (DC-SIGN) signaling](https://reactome.org/content/detail/R-HSA-5621575) | curated |
| [GP1b-IX-V activation signalling](https://reactome.org/content/detail/R-HSA-430116) | curated |
| [IFNG signaling activates MAPKs](https://reactome.org/content/detail/R-HSA-9732724) | curated |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | curated |
| [Negative feedback regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5674499) | curated |
| [Negative regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5675221) | curated |
| [RAF activation](https://reactome.org/content/detail/R-HSA-5673000) | curated |
| [Rap1 signalling](https://reactome.org/content/detail/R-HSA-392517) | curated |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

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

**Molecular function:** protein kinase activity, protein serine/threonine kinase activity, adenylate cyclase activator activity, enzyme binding, identical protein binding.

**Biological process:** negative regulation of cell population proliferation, negative regulation of protein-containing complex assembly, positive regulation of peptidyl-serine phosphorylation, negative regulation of apoptotic process, positive regulation of MAPK cascade.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-19.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-09-19 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype.

## Similar variants {#similar}

Related RAF1 variant pages (same residue, condition, or type): [RAF1 p.Ser233Phe](/variant/raf1-p-ser233phe), [RAF1 p.Pro261His](/variant/raf1-p-pro261his), [RAF1 p.Pro261Leu](/variant/raf1-p-pro261leu), [RAF1 c.207+5G>T](/variant/raf1-c-207-plus-5g-t), [RAF1 c.834+4A>C](/variant/raf1-c-834-plus-4a-c), [RAF1 c.-4A>C](/variant/raf1-c-minus-4a-c), [RAF1 p.Ala119Val](/variant/raf1-p-ala119val), [RAF1 p.Ala566Thr](/variant/raf1-p-ala566thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 1756538). 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.*