# NM_006939.4(SOS2):c.2241C>T (p.Ser747=)

https://sugi.bio/variant/sos2-p-ser747

## Summary

**SOS2 p.Ser747= (c.2241C>T)** is classified **Uncertain significance** in SOS2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-09-03). Very rare (popmax 0.00119%, nfe); Associated with Noonan syndrome 9.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1230203021 · 2 submitters · 1 linked condition · very rare (popmax 0.00119%, nfe)

## For patients & families {#patients}

This is a change in the SOS2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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.Ser747= |
| Coding change (HGVS c.) | c.2241C>T |
| MANE Select transcript | [NM_006939](https://www.ncbi.nlm.nih.gov/nuccore/NM_006939) |
| dbSNP | [rs1230203021](https://www.ncbi.nlm.nih.gov/snp/rs1230203021/) |
| Variant type | single nucleotide variant |
| Location | chr14:50150151-50150151 (GRCh38) |
| ClinVar | [VCV2195748](https://www.ncbi.nlm.nih.gov/clinvar/variation/2195748/) |

**All HGVS expressions:** `NC_000014.8:g.50616869G>A`, `NC_000014.9:g.50150151G>A`, `NG_051073.1:g.86543C>T`, `NM_001411020.1:c.2142C>T`, `NM_006939.4:c.2241C>T`

## 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 gain** (Δ 0.57) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.98, GERP 1.07, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 18.39**. 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 **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.57**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.57**.
- Pangolin: Δ**0.46** (gain), gain 0.46 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00119%** (nfe) · FAF95 0.000689% · FAF99 0.000539% · 14/1,179,150 in the highest group · 14/1,460,916 alleles overall — very rare (popmax 0.00119%, nfe).

*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, triplosensitivity 0 (0–3 scale). *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}


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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-03.

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

**Submission history:** 2 submissions (2021–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-03 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-01-20 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Noonan syndrome 9, SOS2-related disorder, SOS2-related condition.

## Similar variants {#similar}

Related SOS2 variant pages (same residue, condition, or type): [SOS2 p.Ser747Asn](/variant/sos2-p-ser747asn), [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), [SOS2 p.Met267Arg](/variant/sos2-p-met267arg).

### 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 2195748). 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.*