Is AGXT p.Ala40fs (c.116_117dup) pathogenic?

AGXT p.Ala40fs (c.116117dup) is classified Pathogenic/Likely pathogenic in AGXT (ClinVar, Multiple submitters, 6 submitters; last evaluated 2023-09-01). Very rare (popmax 0.00161%, nfe); Associated with primary hyperoxaluria.

What condition is associated with AGXT p.Ala40fs (c.116_117dup)?

AGXT p.Ala40fs (c.116_117dup) is associated with primary hyperoxaluria, primary hyperoxaluria type 1 (ClinVar).

How common is AGXT p.Ala40fs (c.116_117dup) in the general population?

AGXT p.Ala40fs (c.116_117dup) is very rare (popmax 0.00161%, nfe) (gnomAD).

How is Primary hyperoxaluria inherited?

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

AGXT p.Ala40fs

c.116_117dup · rs180177166 · VCV204175

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Conditions

primary hyperoxaluria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.3	GERP 0.11, phastCons 1
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00161% European (non-Finnish) · 19/1,180,034 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00161% 26/1,612,922 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,495
Finnishnot grpmax-eligible	0.00318%	31,457
European (non-Finnish)grpmax	0.00161%	62,107

Remaining individuals 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.Ala40fs
Coding: c.116_117dup
MANE Select: NM_000030
dbSNP: rs180177166
Type: Duplication
Location: chr2:240868980 (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 40: an α-helix

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

Disease context

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

Also linked: primary hyperoxaluria type 1

For Primary hyperoxaluria (Orphanet):

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

Similar variants

AGXT c.166-1_172dup Pathogenic ★★ same condition
AGXT p.Asp243fs Pathogenic ★★ same condition
AGXT p.Tyr270fs Pathogenic/Likely pathogenic ★★ same condition
AGXT p.Ala13fs Likely pathogenic ★ same condition
AGXT p.Asn72fs Likely pathogenic ★ same condition
AGXT p.Glu117fs Pathogenic ★ same condition
AGXT p.Leu14fs Pathogenic ★ same condition
AGXT p.Leu90fs 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-ala40fs (accessed [today's date]).

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