# NM_005763.4(AASS):c.2076dup (p.Pro693fs)

https://sugi.bio/variant/aass-p-pro693fs

## Summary

**AASS p.Pro693fs (c.2076dup)** is classified **Pathogenic/Likely pathogenic** in AASS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-21). Very rare (popmax 0.0022%, sas); Associated with hyperlysinemia.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs768943469 · 2 submitters · 1 linked condition · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the AASS gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to hyperlysinemia.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Diagnostic panels | AASS is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Hyperlysinemia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Microcephaly — Frequent (79-30%)
- Atypical behavior — Frequent (79-30%)
- Short attention span — Frequent (79-30%)
- Delayed speech and language development — Frequent (79-30%)
- Intellectual disability — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Global developmental delay — Frequent (79-30%)
- Hyperammonemia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002828/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AASS](https://sugi.bio/atlas/gene/AASS/) |
| Protein change (HGVS p.) | p.Pro693fs |
| Coding change (HGVS c.) | c.2076dup |
| MANE Select transcript | [NM_005763](https://www.ncbi.nlm.nih.gov/nuccore/NM_005763) |
| dbSNP | [rs768943469](https://www.ncbi.nlm.nih.gov/snp/rs768943469/) |
| Variant type | Duplication |
| Location | chr7:122086119-122086120 (GRCh38) |
| ClinVar | [VCV3899464](https://www.ncbi.nlm.nih.gov/clinvar/variation/3899464/) |

**All HGVS expressions:** `NC_000007.13:g.121726180dup`, `NC_000007.14:g.122086126dup`, `NG_008140.2:g.63171dup`, `NM_005763.4:c.2076dup`, `NM_005763.4:c.2076dupT`

## Computational & population evidence {#evidence}

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

- **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 11.579, GERP 1.73, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.948, pLI 4.5131e-21. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 19 of 24**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 35.0**. 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 duplication 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 **0.0022%** (sas) · FAF95 0.000615% · FAF99 0.000474% · 2/91,040 in the highest group · 15/1,613,140 alleles overall — very rare (popmax 0.0022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0022% | 45,520 |
| European (non-Finnish) | 0.0011% | 90,750 |

*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}

**AASS** population constraint: LOEUF 0.948, pLI 4.5131e-21, missense-Z 1.5093; 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):

- **hyperlysinemia** — Definitive (AR)

## Protein context {#protein}

Residue **693** lies in the 'saccharopine dehydrogenase' region.

AlphaFold model confidence (whole protein): pLDDT 90.73, 77% of residues very-high.

**9 experimental structure(s)** (PDB): [5L76](https://www.rcsb.org/structure/5L76), [5L78](https://www.rcsb.org/structure/5L78), [5O1N](https://www.rcsb.org/structure/5O1N), [5O1O](https://www.rcsb.org/structure/5O1O), [5O1P](https://www.rcsb.org/structure/5O1P), [8DDA](https://www.rcsb.org/structure/8DDA).

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

*Describes the biological roles of AASS (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:** AASS's established molecular role includes saccharopine dehydrogenase (NADP+, L-lysine-forming) activity. p.Pro693fs falls in the saccharopine dehydrogenase region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Lysine catabolism](https://reactome.org/content/detail/R-HSA-71064) | curated |

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

**Molecular function:** saccharopine dehydrogenase (NADP+, L-lysine-forming) activity, saccharopine dehydrogenase (NAD+, L-glutamate-forming) activity.

**Biological process:** obsolete lysine catabolic process.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-21.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2024–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-11-18 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-21 |

## Associated conditions {#conditions}

[hyperlysinemia](https://sugi.bio/atlas/disease/hyperlysinemia/).

**Reported phenotype names (ClinVar):** Hyperlysinemia, not provided, none provided, Hyperlysinemias.

## Similar variants {#similar}

Related AASS variant pages (same residue, condition, or type): [AASS p.Ala733fs](/variant/aass-p-ala733fs), [AASS p.Tyr302fs](/variant/aass-p-tyr302fs), [AASS c.1767-1G>A](/variant/aass-c-1767-minus-1g-a), [AASS p.Arg132His](/variant/aass-p-arg132his), [AASS p.Arg132Cys](/variant/aass-p-arg132cys), [AASS p.Gln921Arg](/variant/aass-p-gln921arg), [AASS p.Leu465Val](/variant/aass-p-leu465val), [AASS p.Lys780Thr](/variant/aass-p-lys780thr).

### 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 3899464). 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.*