# NM_017707.4(ASAP3):c.1566T>G (p.Ser522Arg)

https://sugi.bio/variant/asap3-p-ser522arg

## Summary

**ASAP3 p.Ser522Arg (c.1566T>G)** is classified **Uncertain significance** in ASAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-13). AlphaMissense: likely pathogenic (0.9309); Ultra-rare (popmax 0.011%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.011%, sas)

## For patients & families {#patients}

This is a change in the ASAP3 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 | [ASAP3](https://sugi.bio/atlas/gene/ASAP3/) |
| Protein change (HGVS p.) | p.Ser522Arg |
| Coding change (HGVS c.) | c.1566T>G |
| MANE Select transcript | [NM_017707](https://www.ncbi.nlm.nih.gov/nuccore/NM_017707) |
| Variant type | single nucleotide variant |
| Location | chr1:23436565-23436565 (GRCh38) |
| ClinVar | [VCV3950818](https://www.ncbi.nlm.nih.gov/clinvar/variation/3950818/) |

**All HGVS expressions:** `NC_000001.10:g.23763058A>C`, `NC_000001.11:g.23436565A>C`, `NM_001143778.2:c.1539T>G`, `NM_017707.4:c.1566T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9309)
- REVEL 0.462 (indeterminate)
- SaProt LLR -12.1 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.111, GERP 1.1, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in ASAP3 (of 5,299 modeled).
- CADD: **PHRED 23.7**. 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 0.87** across the covering region of the MANE Select transcript (23,429,859–23,484,133), spanning 54,274 bp. Chi-square p 1.4e-05. 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 **0.23**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 5 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.22** (loss), gain 0.00 / loss 0.22. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.011%** (sas) · FAF95 0.00594% · FAF99 0.00453% · 10/91,078 in the highest group · 11/1,613,484 alleles overall — ultra-rare (popmax 0.011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.011% | 9,108 |
| European (non-Finnish) | 8.48e-05% | 1,179,855 |

*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}

**ASAP3** population constraint: LOEUF 0.864, pLI 1.5967e-20, missense-Z 1.818. *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 **522** lies in the arf-gap domain.

AlphaFold model confidence (whole protein): pLDDT 74.62, 48% of residues very-high.

**4 experimental structure(s)** (PDB): [2B0O](https://www.rcsb.org/structure/2B0O), [3LVQ](https://www.rcsb.org/structure/3LVQ), [3LVR](https://www.rcsb.org/structure/3LVR), [9JIH](https://www.rcsb.org/structure/9JIH).

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

*Describes the biological roles of ASAP3 (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:** ASAP3's established molecular role includes GTPase activator activity. p.Ser522Arg falls in the arf-gap domain.


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

**Molecular function:** GTPase activator activity.

**Biological process:** cell migration, positive regulation of GTPase activity, regulation of stress fiber assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-13.

**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 | 2025-05-13 |

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

## Similar variants {#similar}

Related ASAP3 variant pages (same residue, condition, or type): [ASAP3 p.Asp314=](/variant/asap3-p-asp314), [ASAP3 p.Glu377Ala](/variant/asap3-p-glu377ala), [ASAP3 p.Leu147=](/variant/asap3-p-leu147), [ASAP3 p.Ala103Thr](/variant/asap3-p-ala103thr), [ASAP3 p.Ala221Thr](/variant/asap3-p-ala221thr), [ASAP3 p.Ala244Val](/variant/asap3-p-ala244val), [ASAP3 p.Ala415Val](/variant/asap3-p-ala415val), [ASAP3 p.Ala566Thr](/variant/asap3-p-ala566thr).

### 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 3950818). 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.*