# NM_006944.3(SPP2):c.541C>A (p.Arg181=)

https://sugi.bio/variant/spp2-p-arg181

## Summary

**SPP2 p.Arg181= (c.541C>A)** is classified **Uncertain significance** in SPP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-05). Very rare (popmax 8.48e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs375462993 · 1 submitter · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the SPP2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [SPP2](https://sugi.bio/atlas/gene/SPP2/) |
| Protein change (HGVS p.) | p.Arg181= |
| Coding change (HGVS c.) | c.541C>A |
| MANE Select transcript | [NM_006944](https://www.ncbi.nlm.nih.gov/nuccore/NM_006944) |
| dbSNP | [rs375462993](https://www.ncbi.nlm.nih.gov/snp/rs375462993/) |
| Variant type | single nucleotide variant |
| Location | chr2:234067265-234067265 (GRCh38) |
| ClinVar | [VCV1525553](https://www.ncbi.nlm.nih.gov/clinvar/variation/1525553/) |

**All HGVS expressions:** `NC_000002.11:g.234975909C>A`, `NC_000002.12:g.234067265C>A`, `NG_008668.1:g.21564C>A`, `NM_006944.3:c.541C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.48) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -0.067, GERP 2.41 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.897**. 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 **0.45**, donor loss **0.48**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.48**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.52** (loss), gain 0.00 / loss 0.52. 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 **8.48e-05%** (nfe) · 1/1,179,934 in the highest group · 2/1,613,986 alleles overall — very rare (popmax 8.48e-05%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,604 |
| European (non-Finnish) (grpmax) | 8.48e-05% | 1,179,934 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**SPP2** population constraint: LOEUF 1.655, pLI 1.3577e-12, missense-Z 0.19024; 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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 69.68, 36% of residues very-high.

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

*Describes the biological roles of SPP2 (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}

SPP2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-11-05.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-11-05 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related SPP2 variant pages (same residue, condition, or type): [SPP2 p.Arg181Gln](/variant/spp2-p-arg181gln), [SPP2 p.Arg181Trp](/variant/spp2-p-arg181trp), [SPP2 c.210+1G>A](/variant/spp2-c-210-plus-1g-a), [SPP2 c.500-1G>T](/variant/spp2-c-500-minus-1g-t), [SPP2 c.86-1G>T](/variant/spp2-c-86-minus-1g-t), [SPP2 p.Ala101Thr](/variant/spp2-p-ala101thr), [SPP2 p.Arg133Cys](/variant/spp2-p-arg133cys), [SPP2 p.Arg161Ile](/variant/spp2-p-arg161ile).

### 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 1525553). 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.*