Is AGXT p.Leu166Pro (c.497T>C) pathogenic?

AGXT p.Leu166Pro (c.497T>C) is classified Uncertain significance in AGXT (ClinVar, Single submitter, 2 submitters; last evaluated 2024-05-17). AlphaMissense: likely pathogenic (0.6063); Very rare (popmax 0.00173%, amr); Associated with primary hyperoxaluria type 1.

What condition is associated with AGXT p.Leu166Pro (c.497T>C)?

AGXT p.Leu166Pro (c.497T>C) is associated with primary hyperoxaluria type 1 (ClinVar).

How common is AGXT p.Leu166Pro (c.497T>C) in the general population?

AGXT p.Leu166Pro (c.497T>C) is very rare (popmax 0.00173%, amr) (gnomAD).

How is Primary hyperoxaluria inherited?

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

What do computational predictors say about AGXT p.Leu166Pro (c.497T>C)?

AlphaMissense predicts likely pathogenic (score 0.6063) — an in-silico prediction, not a clinical call.

AGXT p.Leu166Pro

c.497T>C · rs180177230 · VCV204107

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6063 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00173%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary hyperoxaluria type 1

Computational evidence

Protein change
AlphaMissense	0.6063	likely pathogenic
REVEL	0.871	moderately pathogenic-leaning
SaProt	LLR -13.02	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 7.6	GERP 1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 9,952 bp · p 0.92 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00173% Admixed American · 1/57,970 alleles

Filtering AF 0.000184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.001% 16/1,597,644 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0129%	7,749
Admixed Americangrpmax	0.00173%	57,970
South Asian	0.00114%	88,018
European (non-Finnish)	0.000512%	195,466

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: AGXT
Protein: p.Leu166Pro
Coding: c.497T>C
MANE Select: NM_000030
dbSNP: rs180177230
Type: single nucleotide variant
Location: chr2:240871422 (GRCh38)
Gene constraint: LOEUF 1.251 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 98.30 · 17 PDB
Residue 166: a UniProt-annotated variant site (in hp1; associated in cis with l-11 and m-340; results in loss of alanine--glyoxylate aminotransferase activity)

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

Disease context

primary hyperoxaluria type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary hyperoxaluria (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Germany)

Similar variants

AGXT p.Leu166His Uncertain significance ★ ⚠ same residue
AGXT p.Leu166= Likely benign ★ same residue
AGXT c.358+1G>A Pathogenic ★★ same condition
AGXT c.359-2A>G Likely pathogenic ★★ same condition
AGXT c.423+1G>A Pathogenic/Likely pathogenic ★★ same condition
AGXT c.524+2T>A Likely pathogenic ★★ same condition
AGXT c.525-1G>A Pathogenic ★★ same condition
AGXT c.525-2A>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/agxt-p-leu166pro (accessed [today's date]).

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