Is AGXT p.Glu346Lys (c.1036G>A) pathogenic?

AGXT p.Glu346Lys (c.1036G>A) is classified Uncertain significance in AGXT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-12). AlphaMissense: ambiguous (0.4696); Ultra-rare (popmax 0.0165%, mid); Associated with primary hyperoxaluria type 1.

What condition is associated with AGXT p.Glu346Lys (c.1036G>A)?

AGXT p.Glu346Lys (c.1036G>A) is associated with primary hyperoxaluria type 1 (ClinVar).

How common is AGXT p.Glu346Lys (c.1036G>A) in the general population?

AGXT p.Glu346Lys (c.1036G>A) is ultra-rare (popmax 0.0165%, mid) (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.Glu346Lys (c.1036G>A)?

AlphaMissense predicts ambiguous (score 0.4696) — an in-silico prediction, not a clinical call.

AGXT p.Glu346Lys

c.1036G>A · VCV3358971

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4696 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

primary hyperoxaluria type 1

Computational evidence

Protein change
AlphaMissense	0.4696	ambiguous
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -6.38	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP -0.023, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 9,952 bp · p 0.92 · regional, not allelic
Overall
CADD	24.9	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.0024% 35/1,460,982 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.0028%	35,758
Remaining individualsnot grpmax-eligible	0.0016%	62,500

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.Glu346Lys
Coding: c.1036G>A
MANE Select: NM_000030
Type: single nucleotide variant
Location: chr2:240878115 (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 346: a β-strand

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.Glu346= 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
AGXT c.595+1G>T 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-glu346lys (accessed [today's date]).

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