# NM_018136.5(ASPM):c.5863dup (p.Gln1955fs)

https://sugi.bio/variant/aspm-p-gln1955fs

## Summary

**ASPM p.Gln1955fs (c.5863dup)** is classified **Pathogenic** in ASPM (ClinVar, Single submitter, 1 submitter). No gnomAD frequency available for this variant; Associated with microcephaly 1, primary, autosomal recessive.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1571600860 · 1 submitter · 1 linked condition · 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, and is linked to microcephaly 1, primary, autosomal recessive.

*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/0015198/index) · [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.Gln1955fs |
| Coding change (HGVS c.) | c.5863dup |
| MANE Select transcript | [NM_018136](https://www.ncbi.nlm.nih.gov/nuccore/NM_018136) |
| dbSNP | [rs1571600860](https://www.ncbi.nlm.nih.gov/snp/rs1571600860/) |
| Variant type | Duplication |
| Location | chr1:197103387-197103388 (GRCh38) |
| ClinVar | [VCV694714](https://www.ncbi.nlm.nih.gov/clinvar/variation/694714/) |

**All HGVS expressions:** `NC_000001.10:g.197072518dup`, `NC_000001.11:g.197103388dup`, `NG_015867.1:g.48307dup`, `NM_001206846.2:c.4066-7224dup`, `NM_018136.5:c.5863dup`

## 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 4.18, GERP -0.944, phastCons 1 — 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 18 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)

## Protein context {#protein}

Residue **1955** lies in the iq 12 domain.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn | Pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[microcephaly 1, primary, autosomal recessive](https://sugi.bio/atlas/disease/microcephaly-1-primary-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Microcephaly 1, primary, autosomal recessive, PREMATURE CHROMOSOME CONDENSATION SYNDROME, PCC SYNDROME, PREMATURE CHROMOSOME CONDENSATION WITH MICROCEPHALY AND MENTAL RETARDATION.

## Similar variants {#similar}

Related ASPM variant pages (same residue, condition, or type): [ASPM p.Arg3244Ter](/variant/aspm-p-arg3244ter), [ASPM p.Arg980Ter](/variant/aspm-p-arg980ter), [ASPM p.Lys2595fs](/variant/aspm-p-lys2595fs), [ASPM p.Trp989Ter](/variant/aspm-p-trp989ter), [ASPM p.Asn2734fs](/variant/aspm-p-asn2734fs), [ASPM p.Leu1063Ter](/variant/aspm-p-leu1063ter), [ASPM p.Arg2184fs](/variant/aspm-p-arg2184fs), [ASPM p.Gln2377fs](/variant/aspm-p-gln2377fs).

### 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 694714). 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.*