Is AGA p.Cys163Ser (c.488G>C) pathogenic?

AGA p.Cys163Ser (c.488G>C) is classified Pathogenic in AGA (ClinVar, Multiple submitters, 9 submitters; last evaluated 2024-11-23). AlphaMissense: likely pathogenic (0.9579); Very rare (popmax 0.00316%, nfe); Associated with AGA-related disorder.

What condition is associated with AGA p.Cys163Ser (c.488G>C)?

AGA p.Cys163Ser (c.488G>C) is associated with AGA-related disorder, aspartylglucosaminuria (ClinVar).

How common is AGA p.Cys163Ser (c.488G>C) in the general population?

AGA p.Cys163Ser (c.488G>C) is very rare (popmax 0.00316%, nfe) (gnomAD).

What do computational predictors say about AGA p.Cys163Ser (c.488G>C)?

AlphaMissense predicts likely pathogenic (score 0.9579) — an in-silico prediction, not a clinical call.

AGA p.Cys163Ser

c.488G>C · rs121964904 · VCV219

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9579 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00316%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AGA-related disorder

Computational evidence

Protein change
AlphaMissense	0.9579	likely pathogenic ✓ concordant with ClinVar · top 3% in AGA
REVEL	0.865	moderately pathogenic-leaning
SaProt	LLR -13.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 11 kb · p 0.64 · regional, not allelic
Overall
CADD	26.7	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 0.00316% European (non-Finnish) · 37/1,169,066 alleles

Filtering AF 0.00233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00204%

Overall 0.0346% 555/1,602,166 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.767%	130
Remaining individualsnot grpmax-eligible	0.0435%	2,301
European (non-Finnish)grpmax	0.00316%	31,596

Finnish 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: AGA
Protein: p.Cys163Ser
Coding: c.488G>C
MANE Select: NM_000027
dbSNP: rs121964904
Type: single nucleotide variant
Location: chr4:177438764 (GRCh38)
Gene constraint: LOEUF 0.938 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.41 · 2 PDB
Residue 163: a disulfide bond; a UniProt-annotated variant site (in agu; most frequent mutation; abolishes autocatalytic cleavage and enzyme activity)

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

Disease context

AGA-related disorder

Also linked: aspartylglucosaminuria

Similar variants

AGA p.Cys163= Likely benign ★ same residue
AGA c.127+1G>A Likely pathogenic ★★ same condition
AGA c.127+1G>T Likely pathogenic ★★ same condition
AGA c.128-2A>G Pathogenic ★★ same condition
AGA c.281+1G>T Likely pathogenic ★★ same condition
AGA c.395-8A>G Pathogenic/Likely pathogenic ★★ same condition
AGA c.508-2A>C Likely pathogenic ★★ same condition
AGA c.508-2A>G Likely pathogenic ★★ 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/aga-p-cys163ser (accessed [today's date]).

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