Is AGA p.Phe75Ser (c.224T>C) pathogenic?

AGA p.Phe75Ser (c.224T>C) is classified Uncertain significance in AGA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-04-16). AlphaMissense: ambiguous (0.3988); Absent from gnomAD v4.1; Associated with aspartylglucosaminuria.

What condition is associated with AGA p.Phe75Ser (c.224T>C)?

AGA p.Phe75Ser (c.224T>C) is associated with aspartylglucosaminuria (ClinVar).

How common is AGA p.Phe75Ser (c.224T>C) in the general population?

AGA p.Phe75Ser (c.224T>C) is absent from gnomAD v4.1 (gnomAD).

How is Aspartylglucosaminuria inherited?

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

What do computational predictors say about AGA p.Phe75Ser (c.224T>C)?

AlphaMissense predicts ambiguous (score 0.3988) — an in-silico prediction, not a clinical call.

AGA p.Phe75Ser

c.224T>C · rs757065230 · VCV991950

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3988 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

aspartylglucosaminuria

Computational evidence

Protein change
AlphaMissense	0.3988	ambiguous
REVEL	0.615	indeterminate
SaProt	LLR -9.41	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 11 kb · p 0.64 · regional, not allelic
Overall
CADD	25.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AGA
Protein: p.Phe75Ser
Coding: c.224T>C
MANE Select: NM_000027
dbSNP: rs757065230
Type: single nucleotide variant
Location: chr4:177440330 (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 75: a β-strand

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

Disease context

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

For Aspartylglucosaminuria (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Australia)

Similar variants

AGA p.Phe75Cys Uncertain significance ★ ⚠ 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-phe75ser (accessed [today's date]).

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