# NM_005633.4(SOS1):c.3709C>G (p.Pro1237Ala)

https://sugi.bio/variant/sos1-p-pro1237ala

## Summary

**SOS1 p.Pro1237Ala (c.3709C>G)** is classified **Conflicting classifications of pathogenicity** in SOS1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-07). AlphaMissense: likely benign (0.0785); Ultra-rare (popmax 0.0495%, mid); Associated with Noonan syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs371408734 · 9 submitters · 5 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0495%, mid)

## For patients & families {#patients}

This is a change in the SOS1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 9 submitters, and is linked to Noonan syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 27 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010955/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SOS1](https://sugi.bio/atlas/gene/SOS1/) |
| Protein change (HGVS p.) | p.Pro1237Ala |
| Coding change (HGVS c.) | c.3709C>G |
| MANE Select transcript | [NM_005633](https://www.ncbi.nlm.nih.gov/nuccore/NM_005633) |
| dbSNP | [rs371408734](https://www.ncbi.nlm.nih.gov/snp/rs371408734/) |
| Variant type | single nucleotide variant |
| Location | chr2:38986117-38986117 (GRCh38) |
| ClinVar | [VCV336015](https://www.ncbi.nlm.nih.gov/clinvar/variation/336015/) |

**All HGVS expressions:** `LRG_754:g.139347C>G`, `LRG_754t1:c.3709C>G`, `NC_000002.11:g.39213258G>C`, `NC_000002.12:g.38986117G>C`, `NG_007530.1:g.139347C>G`, `NM_001382394.1:c.3688C>G`, `NM_001382395.1:c.3664C>G`, `NM_005633.4:c.3709C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0785)
- REVEL 0.438 (indeterminate)
- SaProt LLR -7.587 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 10.039, GERP 3.7, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.7**. 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 0.95** across the covering region of the MANE Select transcript (38,985,827–38,995,251), spanning 9,424 bp. Chi-square p 0.35. 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 (gnomAD v4.1): grpmax **0.0495%** (mid) · FAF95 0.0134% · FAF99 0.00736% · 3/6,058 in the highest group · 145/1,613,836 alleles overall — ultra-rare (popmax 0.0495%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0495% | 2,019 |
| African / African-American | 0.0133% | 7,497 |
| South Asian | 0.0121% | 8,279 |
| European (non-Finnish) | 0.00932% | 10,726 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,498 |
| Admixed American | 0.005% | 19,994 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,006 |
| East Asian | 0.00223% | 44,852 |

*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}

**SOS1** population constraint: LOEUF 0.288, pLI 1, missense-Z 2.3433; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/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):

- **nonsyndromic genetic hearing loss** — Moderate (AR)
- **Noonan syndrome** — Definitive (AD)
- **Costello syndrome** — Disputed (AD)
- **cardiofaciocutaneous syndrome** — Disputed (AD)

## Protein context {#protein}

Residue **1237** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 77.12, 48% of residues very-high.

**92 experimental structure(s)** (PDB): [1AWE](https://www.rcsb.org/structure/1AWE), [1BKD](https://www.rcsb.org/structure/1BKD), [1DBH](https://www.rcsb.org/structure/1DBH), [1NVU](https://www.rcsb.org/structure/1NVU), [1NVV](https://www.rcsb.org/structure/1NVV), [1NVW](https://www.rcsb.org/structure/1NVW).

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

*Describes the biological roles of SOS1 (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:** SOS1's established molecular role includes guanyl-nucleotide exchange factor activity. p.Pro1237Ala falls in the disordered region. In Reactome, SOS1 is annotated in disease pathway(s) including **Constitutive Signaling by EGFRvIII**, **Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants**.

**Disease mechanism (Reactome):** SOS1 loss or alteration is curated in [Constitutive Signaling by EGFRvIII](https://reactome.org/content/detail/R-HSA-5637810), [Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants](https://reactome.org/content/detail/R-HSA-1236382), [Constitutive Signaling by Overexpressed ERBB2](https://reactome.org/content/detail/R-HSA-9634285).

### Pathways affected {#pathways}

SOS1 participates in **62 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by EGFRvIII](https://reactome.org/content/detail/R-HSA-5637810) | curated |
| ⚕ [Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants](https://reactome.org/content/detail/R-HSA-1236382) | curated |
| ⚕ [Constitutive Signaling by Overexpressed ERBB2](https://reactome.org/content/detail/R-HSA-9634285) | curated |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| ⚕ [Signaling by ERBB2 ECD mutants](https://reactome.org/content/detail/R-HSA-9665348) | curated |
| ⚕ [Signaling by ERBB2 KD Mutants](https://reactome.org/content/detail/R-HSA-9664565) | curated |
| ⚕ [Signaling by ERBB2 TMD/JMD mutants](https://reactome.org/content/detail/R-HSA-9665686) | curated |
| ⚕ [Signaling by FGFR1 in disease](https://reactome.org/content/detail/R-HSA-5655302) | curated |
| ⚕ [Signaling by FGFR2 in disease](https://reactome.org/content/detail/R-HSA-5655253) | curated |
| ⚕ [Signaling by FGFR3 in disease](https://reactome.org/content/detail/R-HSA-5655332) | curated |
| ⚕ [Signaling by FGFR4 in disease](https://reactome.org/content/detail/R-HSA-5655291) | curated |
| ⚕ [Signaling by FLT3 ITD and TKD mutants](https://reactome.org/content/detail/R-HSA-9703648) | curated |
| ⚕ [Signaling by FLT3 fusion proteins](https://reactome.org/content/detail/R-HSA-9703465) | curated |
| ⚕ [Signaling by PDGFRA extracellular domain mutants](https://reactome.org/content/detail/R-HSA-9673770) | curated |
| ⚕ [Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants](https://reactome.org/content/detail/R-HSA-9673767) | curated |
| ⚕ [Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants](https://reactome.org/content/detail/R-HSA-9670439) | curated |
| [DAP12 signaling](https://reactome.org/content/detail/R-HSA-2424491) | curated |
| [Downstream signal transduction](https://reactome.org/content/detail/R-HSA-186763) | curated |
| [EGFR Transactivation by Gastrin](https://reactome.org/content/detail/R-HSA-2179392) | curated |
| [FCERI mediated MAPK activation](https://reactome.org/content/detail/R-HSA-2871796) | curated |
| [FLT3 Signaling](https://reactome.org/content/detail/R-HSA-9607240) | curated |
| [FRS-mediated FGFR1 signaling](https://reactome.org/content/detail/R-HSA-5654693) | curated |
| [FRS-mediated FGFR2 signaling](https://reactome.org/content/detail/R-HSA-5654700) | curated |
| [FRS-mediated FGFR3 signaling](https://reactome.org/content/detail/R-HSA-5654706) | curated |
| [FRS-mediated FGFR4 signaling](https://reactome.org/content/detail/R-HSA-5654712) | curated |
| [G alpha (12/13) signalling events](https://reactome.org/content/detail/R-HSA-416482) | curated |
| [GRB2 events in EGFR signaling](https://reactome.org/content/detail/R-HSA-179812) | curated |
| [GRB2:SOS provides linkage to MAPK signaling for Integrins ](https://reactome.org/content/detail/R-HSA-354194) | curated |
| [Interleukin receptor SHC signaling](https://reactome.org/content/detail/R-HSA-912526) | curated |
| [Interleukin-15 signaling](https://reactome.org/content/detail/R-HSA-8983432) | curated |
| [MET activates RAS signaling](https://reactome.org/content/detail/R-HSA-8851805) | curated |
| [NCAM signaling for neurite out-growth](https://reactome.org/content/detail/R-HSA-375165) | 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 |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [RET signaling](https://reactome.org/content/detail/R-HSA-8853659) | curated |
| [Regulation of KIT signaling](https://reactome.org/content/detail/R-HSA-1433559) | curated |
| [SHC-mediated cascade:FGFR1](https://reactome.org/content/detail/R-HSA-5654688) | curated |
| [SHC-mediated cascade:FGFR2](https://reactome.org/content/detail/R-HSA-5654699) | curated |
| [SHC-mediated cascade:FGFR3](https://reactome.org/content/detail/R-HSA-5654704) | curated |
| [SHC-mediated cascade:FGFR4](https://reactome.org/content/detail/R-HSA-5654719) | curated |
| [SHC1 events in EGFR signaling](https://reactome.org/content/detail/R-HSA-180336) | curated |
| [SHC1 events in ERBB4 signaling](https://reactome.org/content/detail/R-HSA-1250347) | curated |
| [Signal attenuation](https://reactome.org/content/detail/R-HSA-74749) | curated |
| [Signaling by LTK](https://reactome.org/content/detail/R-HSA-9842663) | curated |
| [Signaling by SCF-KIT](https://reactome.org/content/detail/R-HSA-1433557) | curated |
| [Tie2 Signaling](https://reactome.org/content/detail/R-HSA-210993) | curated |
| [Activated NTRK2 signals through FRS2 and FRS3](https://reactome.org/content/detail/R-HSA-9028731) | electronic |
| [Activated NTRK2 signals through RAS](https://reactome.org/content/detail/R-HSA-9026519) | electronic |
| [Activated NTRK3 signals through RAS](https://reactome.org/content/detail/R-HSA-9034864) | electronic |
| [Activation of RAC1](https://reactome.org/content/detail/R-HSA-428540) | electronic |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | electronic |
| [Erythropoietin activates RAS](https://reactome.org/content/detail/R-HSA-9027284) | electronic |
| [FCERI mediated Ca+2 mobilization](https://reactome.org/content/detail/R-HSA-2871809) | electronic |
| [GRB2 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1963640) | electronic |
| [Insulin receptor signalling cascade](https://reactome.org/content/detail/R-HSA-74751) | electronic |
| [Role of LAT2/NTAL/LAB on calcium mobilization](https://reactome.org/content/detail/R-HSA-2730905) | electronic |
| [SHC-related events triggered by IGF1R](https://reactome.org/content/detail/R-HSA-2428933) | electronic |
| [SHC1 events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1250196) | electronic |
| [SOS-mediated signalling](https://reactome.org/content/detail/R-HSA-112412) | electronic |
| [Signaling by CSF1 (M-CSF) in myeloid cells](https://reactome.org/content/detail/R-HSA-9680350) | electronic |
| [Signalling to RAS](https://reactome.org/content/detail/R-HSA-167044) | electronic |

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

**Molecular function:** guanyl-nucleotide exchange factor activity, molecular condensate scaffold activity.

**Biological process:** regulation of transcription by RNA polymerase II, epidermal growth factor receptor signaling pathway, Ras protein signal transduction, T cell activation, regulation of cell population proliferation.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-07.

**Submitter consensus:** conflicting (6 Uncertain significance, 3 Likely benign, 1 Benign).

**Submission history:** 10 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-10-31 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Service de Génétique Moléculaire, Hôpital Robert Debré | Uncertain significance | no assertion criteria provided | clinical testing |  |
| St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-10-07 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-07 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-03-30 |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-10-30 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-09-20 |

## Associated conditions {#conditions}

[Noonan syndrome](https://sugi.bio/atlas/disease/noonan-syndrome/), [fibromatosis, gingival, 1](https://sugi.bio/atlas/disease/fibromatosis-gingival-1/), [Noonan syndrome 4](https://sugi.bio/atlas/disease/noonan-syndrome-4/), [Noonan syndrome and Noonan-related syndrome](https://sugi.bio/atlas/disease/noonan-syndrome-and-noonan-related-syndrome/), [RASopathy](https://sugi.bio/atlas/disease/rasopathy/).

**Reported phenotype names (ClinVar):** Noonan syndrome, Fibromatosis, gingival, 1, Noonan syndrome 4, RASopathy, not specified, not provided, Noonan syndrome and Noonan-related syndrome, Cardiovascular phenotype, Noonan's syndrome, none provided.

## Similar variants {#similar}

Related SOS1 variant pages (same residue, condition, or type): [SOS1 p.Pro1237Thr](/variant/sos1-p-pro1237thr), [SOS1 p.Pro1237Ser](/variant/sos1-p-pro1237ser), [SOS1 p.Pro1237Leu](/variant/sos1-p-pro1237leu), [SOS1 p.Arg552Gly](/variant/sos1-p-arg552gly), [SOS1 p.Arg552Lys](/variant/sos1-p-arg552lys), [SOS1 p.Arg552Met](/variant/sos1-p-arg552met), [SOS1 p.Arg552Ser](/variant/sos1-p-arg552ser), [SOS1 p.Arg552Thr](/variant/sos1-p-arg552thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 336015). 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.*