# NM_018482.4(ASAP1):c.3094T>G (p.Ser1032Ala)

https://sugi.bio/variant/asap1-p-ser1032ala

## Summary

**ASAP1 p.Ser1032Ala (c.3094T>G)** is classified **Uncertain significance** in ASAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.0635); Very rare (popmax 0.00669%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00669%, eas)

## For patients & families {#patients}

This is a change in the ASAP1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [ASAP1](https://sugi.bio/atlas/gene/ASAP1/) |
| Protein change (HGVS p.) | p.Ser1032Ala |
| Coding change (HGVS c.) | c.3094T>G |
| MANE Select transcript | [NM_018482](https://www.ncbi.nlm.nih.gov/nuccore/NM_018482) |
| Variant type | single nucleotide variant |
| Location | chr8:130060677-130060677 (GRCh38) |
| ClinVar | [VCV3950564](https://www.ncbi.nlm.nih.gov/clinvar/variation/3950564/) |

**All HGVS expressions:** `NC_000008.10:g.131072923A>C`, `NC_000008.11:g.130060677A>C`, `NG_030354.1:g.387984T>G`, `NM_001247996.2:c.3073T>G`, `NM_001362924.1:c.3103T>G`, `NM_001362925.2:c.2932T>G`, `NM_001362926.2:c.2923T>G`, `NM_018482.4:c.3094T>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0635)
- REVEL 0.067 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.746 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.315, GERP -3.95, phastCons 0.002 — weakly conserved position
- CADD: **PHRED 16.22**. 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.*
- Regional missense constraint: **o/e 1.06** across the covering region of the MANE Select transcript (130,060,615–130,060,949), spanning 334 bp. Chi-square p 0.49. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00669%** (eas) · FAF95 0.00177% · FAF99 0.000891% · 3/44,874 in the highest group · 3/1,461,894 alleles overall — very rare (popmax 0.00669%, eas).

*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}

**ASAP1** population constraint: LOEUF 0.439, pLI 0.99991, missense-Z 3.4319. *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 **1032** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 72.05, 48% of residues very-high.

**5 experimental structure(s)** (PDB): [2D1X](https://www.rcsb.org/structure/2D1X), [2DA0](https://www.rcsb.org/structure/2DA0), [2ED1](https://www.rcsb.org/structure/2ED1), [2RQT](https://www.rcsb.org/structure/2RQT), [2RQU](https://www.rcsb.org/structure/2RQU).

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

*Describes the biological roles of ASAP1 (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:** ASAP1's established molecular role includes cadherin binding. p.Ser1032Ala falls in the disordered region.


### Pathways affected {#pathways}

ASAP1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [VxPx cargo-targeting to cilium](https://reactome.org/content/detail/R-HSA-5620916) | electronic |

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

**Molecular function:** cadherin binding.

**Biological process:** cilium assembly, protein localization to cilium.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-07.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-07 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ASAP1 variant pages (same residue, condition, or type): [ASAP1 p.Gln263=](/variant/asap1-p-gln263), [ASAP1 p.Ala1035Gly](/variant/asap1-p-ala1035gly), [ASAP1 p.Ala429Val](/variant/asap1-p-ala429val), [ASAP1 p.Ala914Gly](/variant/asap1-p-ala914gly), [ASAP1 p.Arg212His](/variant/asap1-p-arg212his), [ASAP1 p.Arg447Gln](/variant/asap1-p-arg447gln), [ASAP1 p.Arg710Ter](/variant/asap1-p-arg710ter), [ASAP1 p.Arg764Gln](/variant/asap1-p-arg764gln).

### 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 3950564). 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.*