Is AGXT2 p.Val428Ala (c.1283T>C) pathogenic?

AGXT2 p.Val428Ala (c.1283T>C) is classified Uncertain significance in AGXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). AlphaMissense: likely benign (0.2985); Ultra-rare (popmax 0.0383%, amr).

How common is AGXT2 p.Val428Ala (c.1283T>C) in the general population?

AGXT2 p.Val428Ala (c.1283T>C) is ultra-rare (popmax 0.0383%, amr) (gnomAD).

What do computational predictors say about AGXT2 p.Val428Ala (c.1283T>C)?

AlphaMissense predicts likely benign (score 0.2985) — an in-silico prediction, not a clinical call.

AGXT2 p.Val428Ala

c.1283T>C · rs151278208 · VCV2454538

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2985 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0383%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2985	likely benign
REVEL	0.685	pathogenic-leaning
SaProt	LLR -13.39	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 49 kb · p 0.33 · regional, not allelic
Overall
CADD	25.1	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 0.0383% Admixed American · 23/60,008 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.0108% 174/1,614,144 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0383%	2,609
European (non-Finnish)	0.0117%	8,551
Remaining individualsnot grpmax-eligible	0.0112%	8,927
South Asian	0.00439%	22,773
African / African-American	0.00267%	37,476

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: AGXT2
Protein: p.Val428Ala
Coding: c.1283T>C
MANE Select: NM_031900
dbSNP: rs151278208
Type: single nucleotide variant
Location: chr5:35010055 (GRCh38)
Gene constraint: LOEUF 1.185 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.02

Full AGXT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AGXT2 p.Val428Phe Uncertain significance ★ ⚠ same residue
AGXT2 c.1188+1G>A Benign/Likely benign ★★ same type
AGXT2 p.Arg133Cys Benign ★★ same type
AGXT2 p.Arg242Gln Benign ★★ same type
AGXT2 p.Tyr203= Benign ★★ same type
AGXT2 p.Val116= Likely benign ★★ same type
AGXT2 p.Ala183Val Uncertain significance ★ ⚠ same type
AGXT2 p.Ala306Gly Uncertain significance ★ ⚠ same type

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/agxt2-p-val428ala (accessed [today's date]).

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