Is AGA p.Ile172Thr (c.515T>C) pathogenic?

AGA p.Ile172Thr (c.515T>C) is classified Uncertain significance in AGA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-31). AlphaMissense: likely benign (0.0878); Ultra-rare (popmax 0.0165%, mid); Associated with aspartylglucosaminuria.

What condition is associated with AGA p.Ile172Thr (c.515T>C)?

AGA p.Ile172Thr (c.515T>C) is associated with aspartylglucosaminuria (ClinVar).

How common is AGA p.Ile172Thr (c.515T>C) in the general population?

AGA p.Ile172Thr (c.515T>C) is ultra-rare (popmax 0.0165%, mid) (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.Ile172Thr (c.515T>C)?

AlphaMissense predicts likely benign (score 0.0878) — an in-silico prediction, not a clinical call.

AGA p.Ile172Thr

c.515T>C · rs745924498 · VCV558964

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0878 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

aspartylglucosaminuria

Computational evidence

Protein change
AlphaMissense	0.0878	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 0.46, phastCons 0.65
Regional constraint	o/e 1.02	unconstrained · MANE · 11 kb · p 0.64 · regional, not allelic
Overall
CADD	16.37	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,048 alleles

Filtering AF 0.000811% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000656%

Overall 0.00119% 19/1,600,316 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,048
Remaining individualsnot grpmax-eligible	0.00161%	62,052
European (non-Finnish)	0.00137%	72,978
African / African-American	0.00134%	74,626

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.Ile172Thr
Coding: c.515T>C
MANE Select: NM_000027
dbSNP: rs745924498
Type: single nucleotide variant
Location: chr4:177437512 (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 172: a disulfide bond

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.Ile172Met 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-ile172thr (accessed [today's date]).

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