Is AGA p.Phe135Ser (c.404T>C) pathogenic?

AGA p.Phe135Ser (c.404T>C) is classified Likely pathogenic in AGA (ClinVar, Single submitter, 2 submitters; last evaluated 2022-02-22). AlphaMissense: likely pathogenic (0.963); Very rare (popmax 0.000611%, nfe); Associated with aspartylglucosaminuria.

What condition is associated with AGA p.Phe135Ser (c.404T>C)?

AGA p.Phe135Ser (c.404T>C) is associated with aspartylglucosaminuria (ClinVar).

How common is AGA p.Phe135Ser (c.404T>C) in the general population?

AGA p.Phe135Ser (c.404T>C) is very rare (popmax 0.000611%, nfe) (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.Phe135Ser (c.404T>C)?

AlphaMissense predicts likely pathogenic (score 0.963) — an in-silico prediction, not a clinical call.

AGA p.Phe135Ser

c.404T>C · rs386833427 · VCV55946

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.963 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000611%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

aspartylglucosaminuria

Computational evidence

Protein change
AlphaMissense	0.963	likely pathogenic ✓ concordant with ClinVar · top 2% in AGA
REVEL	0.936	strongly pathogenic-leaning
SaProt	LLR -15.62	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 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 11 kb · p 0.64 · regional, not allelic
Overall
CADD	27.7	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 0.000611% European (non-Finnish) · 7/1,146,472 alleles

Filtering AF 0.000254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000163%

Overall 0.000444% 7/1,577,432 alleles · very rare

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.Phe135Ser
Coding: c.404T>C
MANE Select: NM_000027
dbSNP: rs386833427
Type: single nucleotide variant
Location: chr4:177438848 (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 135: a UniProt-annotated variant site (in agu); an α-helix

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 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
AGA c.698+1G>T Pathogenic/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-phe135ser (accessed [today's date]).

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