# NM_015665.6(AAAS):c.787T>C (p.Ser263Pro)

https://sugi.bio/variant/aaas-p-ser263pro

## Summary

**AAAS p.Ser263Pro (c.787T>C)** is classified **Pathogenic/Likely pathogenic** in AAAS (ClinVar, Multiple submitters, 14 submitters; last evaluated 2025-07-17). AlphaMissense: likely pathogenic (0.9852); Very rare (popmax 0.00703%, nfe); Associated with AAAS-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs121918550 · 14 submitters · 3 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00703%, nfe)

## For patients & families {#patients}

This is a change in the AAAS gene that is considered likely disease-causing, submitted by 14 submitters, and is linked to AAAS-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 | [AAAS](https://sugi.bio/atlas/gene/AAAS/) |
| Protein change (HGVS p.) | p.Ser263Pro |
| Coding change (HGVS c.) | c.787T>C |
| MANE Select transcript | [NM_015665](https://www.ncbi.nlm.nih.gov/nuccore/NM_015665) |
| dbSNP | [rs121918550](https://www.ncbi.nlm.nih.gov/snp/rs121918550/) |
| Variant type | single nucleotide variant |
| Location | chr12:53309624-53309624 (GRCh38) |
| ClinVar | [VCV5045](https://www.ncbi.nlm.nih.gov/clinvar/variation/5045/) |

**All HGVS expressions:** `NC_000012.11:g.53703408A>G`, `NC_000012.12:g.53309624A>G`, `NG_016775.1:g.17005T>C`, `NM_001173466.2:c.688T>C`, `NM_015665.6:c.787T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9852) — concordant with the pathogenic call
- REVEL 0.844 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.985 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.109, GERP 2.01, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in AAAS (of 3,162 modeled).
- CADD: **PHRED 29.2**. 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 0.96** across the covering region of the MANE Select transcript (53,307,492–53,321,465), spanning 13,973 bp. Chi-square p 0.27. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00703%** (nfe) · FAF95 0.00579% · FAF99 0.00533% · 83/1,179,936 in the highest group · 123/1,613,720 alleles overall — very rare (popmax 0.00703%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0547% | 1,829 |
| European (non-Finnish) (grpmax) | 0.00703% | 14,216 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,618 |
| African / African-American | 0.00133% | 75,056 |

Finnish 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}

**AAAS** population constraint: LOEUF 0.921, pLI 8.9231e-16, missense-Z 0.88677. *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 **263** lies in a UniProt-annotated variant site (in aaas).

AlphaFold model confidence (whole protein): pLDDT 75.45, 27% of residues very-high.

**2 experimental structure(s)** (PDB): [7R5J](https://www.rcsb.org/structure/7R5J), [7R5K](https://www.rcsb.org/structure/7R5K).

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

*Describes the biological roles of AAAS (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:** AAAS participates in disease-associated pathways. In Reactome, AAAS is annotated in disease pathway(s) including **Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)**, **HCMV Early Events**.

**Disease mechanism (Reactome):** AAAS loss or alteration is curated in [Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)](https://reactome.org/content/detail/R-HSA-5619107), [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690), [HCMV Late Events](https://reactome.org/content/detail/R-HSA-9610379).

### Pathways affected {#pathways}

AAAS participates in **31 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)](https://reactome.org/content/detail/R-HSA-5619107) | curated |
| ⚕ [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690) | curated |
| ⚕ [HCMV Late Events](https://reactome.org/content/detail/R-HSA-9610379) | curated |
| ⚕ [NEP/NS2 Interacts with the Cellular Export Machinery](https://reactome.org/content/detail/R-HSA-168333) | curated |
| ⚕ [NS1 Mediated Effects on Host Pathways](https://reactome.org/content/detail/R-HSA-168276) | curated |
| ⚕ [Rev-mediated nuclear export of HIV RNA](https://reactome.org/content/detail/R-HSA-165054) | curated |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | curated |
| ⚕ [Transport of Ribonucleoproteins into the Host Nucleus](https://reactome.org/content/detail/R-HSA-168271) | curated |
| ⚕ [Viral Messenger RNA Synthesis](https://reactome.org/content/detail/R-HSA-168325) | curated |
| ⚕ [Vpr-mediated nuclear import of PICs](https://reactome.org/content/detail/R-HSA-180910) | curated |
| ⚕ [Nuclear import of Rev protein](https://reactome.org/content/detail/R-HSA-180746) | electronic |
| [IP3 and IP4 transport between cytosol and nucleus](https://reactome.org/content/detail/R-HSA-1855196) | curated |
| [IP6 and IP7 transport between cytosol and nucleus](https://reactome.org/content/detail/R-HSA-1855229) | curated |
| [IPs transport between nucleus and cytosol](https://reactome.org/content/detail/R-HSA-1855170) | curated |
| [ISG15 antiviral mechanism](https://reactome.org/content/detail/R-HSA-1169408) | curated |
| [Nuclear Pore Complex (NPC) Disassembly](https://reactome.org/content/detail/R-HSA-3301854) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [Regulation of Glucokinase by Glucokinase Regulatory Protein](https://reactome.org/content/detail/R-HSA-170822) | curated |
| [Regulation of HSF1-mediated heat shock response](https://reactome.org/content/detail/R-HSA-3371453) | curated |
| [SUMOylation of DNA damage response and repair proteins](https://reactome.org/content/detail/R-HSA-3108214) | curated |
| [SUMOylation of RNA binding proteins](https://reactome.org/content/detail/R-HSA-4570464) | curated |
| [SUMOylation of SUMOylation proteins](https://reactome.org/content/detail/R-HSA-4085377) | curated |
| [SUMOylation of chromatin organization proteins](https://reactome.org/content/detail/R-HSA-4551638) | curated |
| [SUMOylation of ubiquitinylation proteins](https://reactome.org/content/detail/R-HSA-3232142) | curated |
| [Transport of Mature mRNA Derived from an Intronless Transcript](https://reactome.org/content/detail/R-HSA-159231) | curated |
| [Transport of Mature mRNA derived from an Intron-Containing Transcript](https://reactome.org/content/detail/R-HSA-159236) | curated |
| [Transport of the SLBP Dependant Mature mRNA](https://reactome.org/content/detail/R-HSA-159230) | curated |
| [Transport of the SLBP independent Mature mRNA](https://reactome.org/content/detail/R-HSA-159227) | curated |
| [snRNP Assembly](https://reactome.org/content/detail/R-HSA-191859) | curated |
| [tRNA processing in the nucleus](https://reactome.org/content/detail/R-HSA-6784531) | curated |
| [SUMOylation of DNA replication proteins](https://reactome.org/content/detail/R-HSA-4615885) | electronic |

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

**Biological process:** microtubule bundle formation, nucleocytoplasmic transport, mitotic spindle assembly.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-17.

**Submitter consensus:** conflicting (11 Pathogenic, 4 Likely pathogenic).

**Submission history:** 15 submissions (2003–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2003-05-01 |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Pathogenic | criteria provided, single submitter | clinical testing | 2014-06-20 |
| Genetic Services Laboratory, University of Chicago | Likely pathogenic | criteria provided, single submitter | clinical testing | 2016-08-02 |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Pathogenic | criteria provided, single submitter | clinical testing | 2016-01-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-03-09 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-26 |
| SIB Swiss Institute of Bioinformatics | Likely pathogenic | criteria provided, single submitter | curation | 2018-05-31 |
| Clinical Genetics Laboratory, Skane University Hospital Lund | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-05-27 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-06 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-21 |
| MGZ Medical Genetics Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-03-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-14 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-14 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-17 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-17 |

## Associated conditions {#conditions}

[AAAS-related disorder](https://sugi.bio/atlas/disease/aaas-related-disorder/), [hyperreflexia](https://sugi.bio/atlas/disease/hyperreflexia/), [triple-A syndrome](https://sugi.bio/atlas/disease/triple-a-syndrome/).

**Reported phenotype names (ClinVar):** AAAS-related disorder, Glucocorticoid deficiency with achalasia, Babinski sign, Hyperreflexia, Spastic paraparesis, not provided, Inborn genetic diseases, AAAS-related condition, none provided, Achalasia-addisonianism-alacrimia syndrome.

## Similar variants {#similar}

Related AAAS variant pages (same residue, condition, or type): [AAAS c.1331+1G>A](/variant/aaas-c-1331-plus-1g-a), [AAAS c.1331+1G>C](/variant/aaas-c-1331-plus-1g-c), [AAAS c.446+1G>A](/variant/aaas-c-446-plus-1g-a), [AAAS c.446+1G>T](/variant/aaas-c-446-plus-1g-t), [AAAS c.810+1G>A](/variant/aaas-c-810-plus-1g-a), [AAAS c.936-1G>C](/variant/aaas-c-936-minus-1g-c), [AAAS p.Ala167Glu](/variant/aaas-p-ala167glu), [AAAS p.Ala167Val](/variant/aaas-p-ala167val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 5045). 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.*