# NM_018136.5(ASPM):c.718dup (p.Ser240fs)

https://sugi.bio/variant/aspm-p-ser240fs

## Summary

**ASPM p.Ser240fs (c.718dup)** is classified **Pathogenic** in ASPM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-27). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2527405766 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ASPM gene that is reported as disease-causing, but on limited review, 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 | [ASPM](https://sugi.bio/atlas/gene/ASPM/) |
| Protein change (HGVS p.) | p.Ser240fs |
| Coding change (HGVS c.) | c.718dup |
| MANE Select transcript | [NM_018136](https://www.ncbi.nlm.nih.gov/nuccore/NM_018136) |
| dbSNP | [rs2527405766](https://www.ncbi.nlm.nih.gov/snp/rs2527405766/) |
| Variant type | Duplication |
| Location | chr1:197143533-197143534 (GRCh38) |
| ClinVar | [VCV3023119](https://www.ncbi.nlm.nih.gov/clinvar/variation/3023119/) |

**All HGVS expressions:** `NC_000001.10:g.197112664dup`, `NC_000001.11:g.197143534dup`, `NG_015867.1:g.8161dup`, `NM_001206846.2:c.718dup`, `NM_018136.5:c.718dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 (below), not from a missing predictor score.
- Conservation: phyloP 2.548, GERP -2.08, phastCons 0.999 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.766, pLI 3.3385e-55. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 28**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ASPM** population constraint: LOEUF 0.766, pLI 3.3385e-55, missense-Z 0.80711; ClinGen dosage — haploinsufficiency 30, 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):

- **autosomal recessive primary microcephaly** — Definitive (AR)

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-27.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-27 |

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

## Similar variants {#similar}

Related ASPM variant pages (same residue, condition, or type): [ASPM p.Ser240Cys](/variant/aspm-p-ser240cys), [ASPM p.Ser240Phe](/variant/aspm-p-ser240phe), [ASPM p.Arg2184fs](/variant/aspm-p-arg2184fs), [ASPM p.Gln2377fs](/variant/aspm-p-gln2377fs), [ASPM p.Gln2620fs](/variant/aspm-p-gln2620fs), [ASPM p.Ile2445fs](/variant/aspm-p-ile2445fs), [ASPM p.Glu1480dup](/variant/aspm-p-glu1480dup), [ASPM c.10332-20dup](/variant/aspm-c-10332-minus-20dup).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 3023119). 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.*