# NM_020843.4(SCAPER):c.909A>G (p.Val303=)

https://sugi.bio/variant/scaper-p-val303

## Summary

**SCAPER p.Val303= (c.909A>G)** is classified **Likely benign** in SCAPER (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-20). Very rare (popmax 0.00133%, afr); Associated with SCAPER-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · 1 submitter · 1 linked condition · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the SCAPER gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to SCAPER-related disorder.

*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 | [SCAPER](https://sugi.bio/atlas/gene/SCAPER/) |
| Protein change (HGVS p.) | p.Val303= |
| Coding change (HGVS c.) | c.909A>G |
| MANE Select transcript | [NM_020843](https://www.ncbi.nlm.nih.gov/nuccore/NM_020843) |
| Variant type | single nucleotide variant |
| Location | chr15:76774981-76774981 (GRCh38) |
| ClinVar | [VCV3357376](https://www.ncbi.nlm.nih.gov/clinvar/variation/3357376/) |

**All HGVS expressions:** `NC_000015.10:g.76774981T>C`, `NC_000015.9:g.77067322T>C`, `NM_001145923.2:c.171A>G`, `NM_001353009.2:c.909A>G`, `NM_001353010.2:c.507A>G`, `NM_001353011.2:c.507A>G`, `NM_001353012.2:c.507A>G`, `NM_020843.4:c.909A>G`, `NR_148227.2:n.1049A>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 **donor loss** (Δ 0.52) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -2.48, GERP -3.71 — fast-evolving / accelerated position
- CADD: **PHRED 3.657**. 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 **0.52**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss, 3 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  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 (gnomAD v4.1): grpmax **0.00133%** (afr) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/75,040 in the highest group · 3/1,613,848 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00133% | 75,040 |
| European (non-Finnish) | 0.00017% | 589,890 |

*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}

**SCAPER** population constraint: LOEUF 0.666, pLI 2.1156e-11, missense-Z 2.2837. *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):

- **intellectual developmental disorder and retinitis pigmentosa; IDDRP** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 68.35, 25% of residues very-high.

**2 experimental structure(s)** (PDB): [8BPO](https://www.rcsb.org/structure/8BPO), [9HJ1](https://www.rcsb.org/structure/9HJ1).

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-08-20.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-08-20 |

## Associated conditions {#conditions}

[SCAPER-related disorder](https://sugi.bio/atlas/disease/scaper-related-disorder/).

**Reported phenotype names (ClinVar):** SCAPER-related disorder, SCAPER-related condition.

## Similar variants {#similar}

Related SCAPER variant pages (same residue, condition, or type): [SCAPER p.Arg112Ter](/variant/scaper-p-arg112ter), [SCAPER c.1035+1G>C](/variant/scaper-c-1035-plus-1g-c), [SCAPER c.1613+1G>T](/variant/scaper-c-1613-plus-1g-t), [SCAPER p.Arg277Ter](/variant/scaper-p-arg277ter), [SCAPER p.Arg366Ter](/variant/scaper-p-arg366ter), [SCAPER p.Gln551Ter](/variant/scaper-p-gln551ter), [SCAPER p.Glu885Ter](/variant/scaper-p-glu885ter), [SCAPER p.Ser832Ter](/variant/scaper-p-ser832ter).

### 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 3357376). 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.*