# NM_018136.5(ASPM):c.1729_1730del (p.Ser577fs)

https://sugi.bio/variant/aspm-p-ser577fs

## Summary

**ASPM p.Ser577fs (c.1729_1730del)** is classified **Pathogenic/Likely pathogenic** in ASPM (ClinVar, Multiple submitters, 6 submitters; last evaluated 2023-04-11). Very rare (popmax 0.00167%, amr); Associated with microcephaly 5, primary, autosomal recessive.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs199422146 · 6 submitters · 2 linked conditions · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the ASPM gene that is considered likely disease-causing, submitted by 6 submitters, and is linked to microcephaly 5, 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/0015441/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.Ser577fs |
| Coding change (HGVS c.) | c.1729_1730del |
| MANE Select transcript | [NM_018136](https://www.ncbi.nlm.nih.gov/nuccore/NM_018136) |
| dbSNP | [rs199422146](https://www.ncbi.nlm.nih.gov/snp/rs199422146/) |
| Variant type | Microsatellite |
| Location | chr1:197142522-197142523 (GRCh38) |
| ClinVar | [VCV402179](https://www.ncbi.nlm.nih.gov/clinvar/variation/402179/) |

**All HGVS expressions:** `NC_000001.10:g.197111652CT[1]`, `NC_000001.11:g.197142522CT[1]`, `NG_015867.1:g.9170AG[1]`, `NM_001206846.2:c.1729_1730del`, `NM_018136.4:c.1729_1730delAG`, `NM_018136.5:c.1729_1730del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 0.24, GERP -2.74 — weakly conserved position
- 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.
- CADD: **PHRED 25.3**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · FAF95 0.000763% · FAF99 0.000605% · 1/59,998 in the highest group · 17/1,613,796 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,998 |
| African / African-American | 0.00134% | 74,886 |
| European (non-Finnish) | 0.00127% | 78,658 |

*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 **577** lies in the 'disordered' region.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-04-11.

**Submitter consensus:** conflicting (3 Pathogenic, 2 Likely pathogenic, 1 not provided).

**Submission history:** 6 submissions (2020–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Likely pathogenic | criteria provided, single submitter | research |  |
| Service de Génétique Moléculaire, Hôpital Robert Debré | Pathogenic | no assertion criteria provided | clinical testing |  |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2020-03-27 |
| GeneReviews | not provided | no classification provided | literature only |  |
| Genome-Nilou Lab | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-04-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-11-24 |

## Associated conditions {#conditions}

[microcephaly 5, primary, autosomal recessive](https://sugi.bio/atlas/disease/microcephaly-5-primary-autosomal-recessive/), [microcephaly](https://sugi.bio/atlas/disease/microcephaly/).

**Reported phenotype names (ClinVar):** Microcephaly 5, primary, autosomal recessive, Microcephaly, not provided, none provided, ASPM Primary Microcephaly, Microcephaly (disease).

## Similar variants {#similar}

Related ASPM variant pages (same residue, condition, or type): [ASPM p.Arg1315fs](/variant/aspm-p-arg1315fs), [ASPM p.Arg1416_Tyr1417insTer](/variant/aspm-p-arg1416-tyr1417inster), [ASPM p.Arg1576fs](/variant/aspm-p-arg1576fs), [ASPM p.Arg2229fs](/variant/aspm-p-arg2229fs), [ASPM p.Asn653fs](/variant/aspm-p-asn653fs), [ASPM p.Gln2836fs](/variant/aspm-p-gln2836fs), [ASPM p.Glu385fs](/variant/aspm-p-glu385fs), [ASPM p.Ile2113fs](/variant/aspm-p-ile2113fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 402179). 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.*