Is AASS p.Pro560Ser (c.1678C>T) pathogenic?

AASS p.Pro560Ser (c.1678C>T) is classified Likely benign in AASS (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-21). AlphaMissense: likely benign (0.1925); Rare (popmax 0.76%, nfe); Associated with hyperlysinemia.

What condition is associated with AASS p.Pro560Ser (c.1678C>T)?

AASS p.Pro560Ser (c.1678C>T) is associated with hyperlysinemia (ClinVar).

How common is AASS p.Pro560Ser (c.1678C>T) in the general population?

AASS p.Pro560Ser (c.1678C>T) is rare (popmax 0.76%, nfe) (gnomAD).

How is Hyperlysinemia inherited?

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

What do computational predictors say about AASS p.Pro560Ser (c.1678C>T)?

AlphaMissense predicts likely benign (score 0.1925) — an in-silico prediction, not a clinical call.

AASS p.Pro560Ser

c.1678C>T · rs74882337 · VCV377290

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1925 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.76%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperlysinemia

Computational evidence

Protein change
AlphaMissense	0.1925	likely benign
REVEL	0.221	benign-leaning
SaProt	LLR -9.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.29	acceptor gain · deltas
Pangolin	Δ0.23	gain · loss 0.14 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 57 kb · p 0.0048 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.76% European (non-Finnish) · 8,968/1,179,726 alleles

Filtering AF 0.747% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.742%

Overall 0.606% 9,781/1,613,710 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	4.61%	22
Ashkenazi Jewishnot grpmax-eligible	0.787%	127
European (non-Finnish)grpmax	0.76%	132
Remaining individualsnot grpmax-eligible	0.394%	254
Finnishnot grpmax-eligible	0.297%	337
African / African-American	0.104%	962
Middle Eastern	0.0495%	2,019
Admixed American	0.0317%	3,156
East Asian	0.00223%	44,872
South Asian	0.0011%	91,078

Amish shows a higher raw frequency than the grpmax group above it. 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.

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.Pro560Ser
Coding: c.1678C>T
MANE Select: NM_005763
dbSNP: rs74882337
Type: single nucleotide variant
Location: chr7:122093136 (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 560: an α-helix; 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

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AASS p.Gln921Arg Uncertain significance ★★ ⚠ same condition
AASS p.Leu465Val Uncertain significance ★★ ⚠ same condition
AASS p.Lys780Thr Uncertain significance ★★ ⚠ same condition
AASS p.Tyr578Cys Uncertain significance ★★ ⚠ same condition
AASS p.Val350Met 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-pro560ser (accessed [today's date]).

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