Is AASS p.Pro693fs (c.2076dup) pathogenic?

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.

What condition is associated with AASS p.Pro693fs (c.2076dup)?

AASS p.Pro693fs (c.2076dup) is associated with hyperlysinemia (ClinVar).

How common is AASS p.Pro693fs (c.2076dup) in the general population?

AASS p.Pro693fs (c.2076dup) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Hyperlysinemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

AASS p.Pro693fs

c.2076dup · rs768943469 · VCV3899464

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

hyperlysinemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 19 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,040 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00093% 15/1,613,140 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,520
European (non-Finnish)	0.0011%	90,750

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AASS
Protein: p.Pro693fs
Coding: c.2076dup
MANE Select: NM_005763
dbSNP: rs768943469
Type: Duplication
Location: chr7:122086119 (GRCh38)
Gene constraint: LOEUF 0.948 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.73 · 9 PDB
Residue 693: the 'saccharopine dehydrogenase' region

Full AASS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyperlysinemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hyperlysinemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

AASS p.Ala733fs Likely pathogenic ★ same condition
AASS p.Tyr302fs Pathogenic ★ same condition
AASS c.1767-1G>A Pathogenic/Likely pathogenic ★★ same condition
AASS p.Arg132His Likely pathogenic ★★ same condition
AASS p.Arg132Cys Uncertain significance ★★ ⚠ same condition
AASS p.Gln921Arg Uncertain significance ★★ ⚠ same condition
AASS p.Leu465Val Uncertain significance ★★ ⚠ same condition
AASS p.Lys780Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/aass-p-pro693fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown