Is AGXT p.Leu43Pro (c.128T>C) pathogenic?

AGXT p.Leu43Pro (c.128T>C) is classified Uncertain significance in AGXT (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-17). AlphaMissense: ambiguous (0.5097); Very rare (popmax 9.02e-05%, nfe); Associated with AGXT-related disorder.

What condition is associated with AGXT p.Leu43Pro (c.128T>C)?

AGXT p.Leu43Pro (c.128T>C) is associated with AGXT-related disorder (ClinVar).

How common is AGXT p.Leu43Pro (c.128T>C) in the general population?

AGXT p.Leu43Pro (c.128T>C) is very rare (popmax 9.02e-05%, nfe) (gnomAD).

What do computational predictors say about AGXT p.Leu43Pro (c.128T>C)?

AlphaMissense predicts ambiguous (score 0.5097) — an in-silico prediction, not a clinical call.

AGXT p.Leu43Pro

c.128T>C · VCV3344672

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5097 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.02e-05%, nfe)

Conditions

AGXT-related disorder

Computational evidence

Protein change
AlphaMissense	0.5097	ambiguous
REVEL	0.5	indeterminate
SaProt	LLR -8.25	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.091	GERP 0.36, phastCons 0.032
Regional constraint	o/e 1.00	unconstrained · MANE · 9,952 bp · p 0.92 · regional, not allelic
Overall
CADD	12.58	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 9.02e-05% European (non-Finnish) · 1/1,108,078 alleles

Overall 7.26e-05% 1/1,376,882 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: AGXT
Protein: p.Leu43Pro
Coding: c.128T>C
MANE Select: NM_000030
Type: single nucleotide variant
Location: chr2:240868993 (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 43: an α-helix

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

Disease context

AGXT-related disorder

Similar variants

AGXT p.Leu43Gln Likely benign ★ same residue
AGXT c.596-2A>G Pathogenic ★★ same condition
AGXT c.680+1G>A Pathogenic/Likely pathogenic ★★ same condition
AGXT c.777-1G>C Pathogenic ★★ same condition
AGXT c.847-3C>G Pathogenic/Likely pathogenic ★★ same condition
AGXT p.Arg111Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
AGXT p.Arg36His Pathogenic/Likely pathogenic ★★ ⚠ same condition
AGXT p.Gly190Arg 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-leu43pro (accessed [today's date]).

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