# NM_001395891.1(CLASP1):c.3861G>A (p.Pro1287=)

https://sugi.bio/variant/clasp1-p-pro1287

## Summary

**CLASP1 p.Pro1287= (c.3861G>A)** is classified **Likely benign** in CLASP1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-05-28). Ultra-rare (popmax 0.0164%, mid); Associated with CLASP1-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs553380975 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0164%, mid)

## For patients & families {#patients}

This is a change in the CLASP1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to CLASP1-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 | [CLASP1](https://sugi.bio/atlas/gene/CLASP1/) |
| Protein change (HGVS p.) | p.Pro1287= |
| Coding change (HGVS c.) | c.3861G>A |
| MANE Select transcript | [NM_001395891](https://www.ncbi.nlm.nih.gov/nuccore/NM_001395891) |
| dbSNP | [rs553380975](https://www.ncbi.nlm.nih.gov/snp/rs553380975/) |
| Variant type | single nucleotide variant |
| Location | chr2:121367676-121367676 (GRCh38) |
| ClinVar | [VCV3043713](https://www.ncbi.nlm.nih.gov/clinvar/variation/3043713/) |

**All HGVS expressions:** `NC_000002.11:g.122125252C>T`, `NC_000002.12:g.121367676C>T`, `NM_001142273.2:c.3621G>A`, `NM_001142274.2:c.3597G>A`, `NM_001207051.2:c.3615G>A`, `NM_001378003.1:c.3702G>A`, `NM_001378004.1:c.3594G>A`, `NM_001378005.1:c.3615G>A`, `NM_001395891.1:c.3861G>A`, `NM_015282.3:c.3798G>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 (below), not from a missing predictor score.
- Conservation: phyloP -7.912, GERP -4.24 — fast-evolving / accelerated position
- CADD: **PHRED 3.362**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.32 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0164%** (mid) · FAF95 0.00478% · FAF99 0.00439% · 1/6,082 in the highest group · 97/1,613,888 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0439% | 2,278 |
| Middle Eastern (grpmax) | 0.0164% | 6,082 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,616 |
| European (non-Finnish) | 0.00593% | 16,856 |
| East Asian | 0.00446% | 22,443 |
| South Asian | 0.00439% | 22,771 |
| Admixed American | 0.00167% | 60,004 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,014 |
| African / African-American | 0.00133% | 74,924 |

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}

**CLASP1** population constraint: LOEUF 0.237, pLI 1, missense-Z 3.481; ClinGen dosage — haploinsufficiency 0, 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.*

## Protein context {#protein}

Residue **1287** lies in the 'interaction with clip2' region; the 'interaction with phldb2 and rsn' region; the 'localization to kinetochores' region.

AlphaFold model confidence (whole protein): pLDDT 69.44, 45% of residues very-high.

**3 experimental structure(s)** (PDB): [4K92](https://www.rcsb.org/structure/4K92), [6MQ5](https://www.rcsb.org/structure/6MQ5), [6MQ7](https://www.rcsb.org/structure/6MQ7).

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

*Describes the biological roles of CLASP1 (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.*

**How this variant is thought to act:** CLASP1's established molecular role includes dystroglycan binding. p.Pro1287= falls in the interaction with clip2 region.


### Pathways affected {#pathways}

CLASP1 participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | curated |
| [Amplification  of signal from unattached  kinetochores via a MAD2  inhibitory signal](https://reactome.org/content/detail/R-HSA-141444) | curated |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [EML4 and NUDC in mitotic spindle formation](https://reactome.org/content/detail/R-HSA-9648025) | curated |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | curated |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | curated |
| [Mitotic Prometaphase](https://reactome.org/content/detail/R-HSA-68877) | curated |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | curated |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | curated |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |
| [Resolution of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2500257) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |
| [Role of ABL in ROBO-SLIT signaling](https://reactome.org/content/detail/R-HSA-428890) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** dystroglycan binding, microtubule binding, kinetochore binding, microtubule plus-end binding.

**Biological process:** microtubule cytoskeleton organization, microtubule bundle formation, obsolete vesicle targeting, microtubule nucleation, negative regulation of microtubule depolymerization, Golgi organization.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-05-28.

**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 | 2019-05-28 |

## Associated conditions {#conditions}

[CLASP1-related disorder](https://sugi.bio/atlas/disease/clasp1-related-disorder/).

**Reported phenotype names (ClinVar):** CLASP1-related disorder, CLASP1-related condition.

## Similar variants {#similar}

Related CLASP1 variant pages (same residue, condition, or type): [CLASP1 p.Pro1287Leu](/variant/clasp1-p-pro1287leu), [CLASP1 c.196-567G>A](/variant/clasp1-c-196-minus-567g-a), [CLASP1 c.196-594G>A](/variant/clasp1-c-196-minus-594g-a), [CLASP1 c.196-605C>T](/variant/clasp1-c-196-minus-605c-t), [CLASP1 n.30G>A](/variant/clasp1-n-30g-a), [RNU4ATAC n.53C>G](/variant/rnu4atac-n-53c-g), [RNU4ATAC n.55G>A](/variant/rnu4atac-n-55g-a), [MAST1 p.Gln1392His](/variant/mast1-p-gln1392his).

### 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 3043713). 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.*