# NM_005475.3(SH2B3):c.1566C>G (p.Pro522=)

https://sugi.bio/variant/sh2b3-p-pro522

## Summary

**SH2B3 p.Pro522= (c.1566C>G)** is classified **Likely benign** in SH2B3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-23). Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the SH2B3 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [SH2B3](https://sugi.bio/atlas/gene/SH2B3/) |
| Protein change (HGVS p.) | p.Pro522= |
| Coding change (HGVS c.) | c.1566C>G |
| MANE Select transcript | [NM_005475](https://www.ncbi.nlm.nih.gov/nuccore/NM_005475) |
| Variant type | single nucleotide variant |
| Location | chr12:111448140-111448140 (GRCh38) |
| ClinVar | [VCV4826764](https://www.ncbi.nlm.nih.gov/clinvar/variation/4826764/) |

**All HGVS expressions:** `LRG_621:g.47193C>G`, `LRG_621t1:c.1566C>G`, `LRG_621t2:c.960C>G`, `LRG_864:g.156537G>C`, `NC_000012.11:g.111885944C>G`, `NC_000012.12:g.111448140C>G`, `NG_011572.3:g.156537G>C`, `NG_021216.1:g.47193C>G`, `NM_001291424.1:c.960C>G`, `NM_005475.3:c.1566C>G`

## 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 **acceptor loss** (Δ 0.35) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -3.606, GERP -3.6 — fast-evolving / accelerated position
- CADD: **PHRED 0.417**. 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 **0.35**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 7 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**SH2B3** population constraint: LOEUF 1.35, pLI 5.0447e-15, missense-Z -3.1608. *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):

- **SH2B3-related immune system disorder** — Definitive (SD)

## Protein context {#protein}

Residue **522** lies in a UniProt-annotated variant site (found in a patient with isolated erythrocytosis; uncertain significance); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 63.45, 19% of residues very-high.

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

*Describes the biological roles of SH2B3 (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}

SH2B3 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [Negative regulation of FLT3](https://reactome.org/content/detail/R-HSA-9706369) | curated |
| [Regulation of KIT signaling](https://reactome.org/content/detail/R-HSA-1433559) | curated |

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

**Biological process:** thrombopoietin-mediated signaling pathway, negative regulation of receptor signaling pathway via JAK-STAT, erythrocyte development, negative regulation of response to cytokine stimulus.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-02-23.

**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 | 2026-02-23 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related SH2B3 variant pages (same residue, condition, or type): [SH2B3 p.Pro522Ala](/variant/sh2b3-p-pro522ala), [SH2B3 p.Pro522Leu](/variant/sh2b3-p-pro522leu), [SH2B3 p.Pro522Thr](/variant/sh2b3-p-pro522thr), [SH2B3 p.Ala161Val](/variant/sh2b3-p-ala161val), [SH2B3 p.Ala174Thr](/variant/sh2b3-p-ala174thr), [SH2B3 p.Ala300Thr](/variant/sh2b3-p-ala300thr), [SH2B3 p.Arg221Met](/variant/sh2b3-p-arg221met), [SH2B3 p.Arg226Trp](/variant/sh2b3-p-arg226trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4826764). 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.*