# NM_006939.4(SOS2):c.2397G>A (p.Pro799=)

https://sugi.bio/variant/sos2-p-pro799

## Summary

**SOS2 p.Pro799= (c.2397G>A)** is classified **Likely benign** in SOS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-06-27). Very rare (popmax 0.00344%, sas); Associated with Noonan syndrome 9.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs770022419 · 5 submitters · 1 linked condition · very rare (popmax 0.00344%, sas)

## For patients & families {#patients}

This is a change in the SOS2 gene that is classified as likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to Noonan syndrome 9.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016137/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SOS2](https://sugi.bio/atlas/gene/SOS2/) |
| Protein change (HGVS p.) | p.Pro799= |
| Coding change (HGVS c.) | c.2397G>A |
| MANE Select transcript | [NM_006939](https://www.ncbi.nlm.nih.gov/nuccore/NM_006939) |
| dbSNP | [rs770022419](https://www.ncbi.nlm.nih.gov/snp/rs770022419/) |
| Variant type | single nucleotide variant |
| Location | chr14:50145584-50145584 (GRCh38) |
| ClinVar | [VCV1301363](https://www.ncbi.nlm.nih.gov/clinvar/variation/1301363/) |

**All HGVS expressions:** `NC_000014.8:g.50612302C>T`, `NC_000014.9:g.50145584C>T`, `NG_051073.1:g.91110G>A`, `NM_006939.2:c.2397G>A`, `NM_006939.4:c.2397G>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 (below), not from a missing predictor score.
- Conservation: phyloP -0.001, GERP -3.8, phastCons 0.046 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.226**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.26 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 **0.00344%** (sas) · FAF95 0.000914% · FAF99 0.000453% · 3/87,230 in the highest group · 10/1,594,020 alleles overall — very rare (popmax 0.00344%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00344% | 29,077 |
| Remaining individuals (not grpmax-eligible) | 0.00162% | 61,618 |
| African / African-American | 0.00135% | 73,818 |
| European (non-Finnish) | 0.000426% | 234,585 |

*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}

**SOS2** population constraint: LOEUF 0.415, pLI 0.99989, missense-Z 1.6667; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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):

- **Noonan syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **799** lies in the ras-gef domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 74.67, 37% of residues very-high.

**11 experimental structure(s)** (PDB): [6EIE](https://www.rcsb.org/structure/6EIE), [8T5G](https://www.rcsb.org/structure/8T5G), [8T5M](https://www.rcsb.org/structure/8T5M), [8T5R](https://www.rcsb.org/structure/8T5R), [8UC9](https://www.rcsb.org/structure/8UC9), [8UF2](https://www.rcsb.org/structure/8UF2).

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

*Describes the biological roles of SOS2 (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.*


### Pathways affected {#pathways}

SOS2 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [G alpha (12/13) signalling events](https://reactome.org/content/detail/R-HSA-416482) | curated |
| [Interleukin-15 signaling](https://reactome.org/content/detail/R-HSA-8983432) | curated |
| [NRAGE signals death through JNK](https://reactome.org/content/detail/R-HSA-193648) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [Activation of RAC1](https://reactome.org/content/detail/R-HSA-428540) | electronic |

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-27.

**Submitter consensus:** unanimous (5/5 Likely benign).

**Submission history:** 5 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2021-09-11 |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing |  |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-07 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-03-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-27 |

## Associated conditions {#conditions}

[Noonan syndrome 9](https://sugi.bio/atlas/disease/noonan-syndrome-9/).

**Reported phenotype names (ClinVar):** Noonan syndrome 9, not specified, SOS2-related disorder, Cardiovascular phenotype, SOS2-related condition, AllHighlyPenetrant.

## Similar variants {#similar}

Related SOS2 variant pages (same residue, condition, or type): [SOS2 p.Pro799Leu](/variant/sos2-p-pro799leu), [SOS2 p.Pro799Ser](/variant/sos2-p-pro799ser), [SOS2 p.Met267Lys](/variant/sos2-p-met267lys), [SOS2 p.Ala1195Val](/variant/sos2-p-ala1195val), [SOS2 p.Arg225Gln](/variant/sos2-p-arg225gln), [SOS2 p.Arg986Lys](/variant/sos2-p-arg986lys), [SOS2 p.Thr1079Ala](/variant/sos2-p-thr1079ala), [SOS2 p.Asn867Ser](/variant/sos2-p-asn867ser).

### 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 2026-10-14); 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 1301363). 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.*