Is AGXT2 p.Cys259Phe (c.776G>T) pathogenic?

AGXT2 p.Cys259Phe (c.776G>T) is classified Uncertain significance in AGXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). AlphaMissense: ambiguous (0.4818); Ultra-rare (popmax 0.0141%, nfe).

How common is AGXT2 p.Cys259Phe (c.776G>T) in the general population?

AGXT2 p.Cys259Phe (c.776G>T) is ultra-rare (popmax 0.0141%, nfe) (gnomAD).

What do computational predictors say about AGXT2 p.Cys259Phe (c.776G>T)?

AlphaMissense predicts ambiguous (score 0.4818) — an in-silico prediction, not a clinical call.

AGXT2 p.Cys259Phe

c.776G>T · VCV3843302

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4818 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0141%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4818	ambiguous
REVEL	0.744	pathogenic-leaning
SaProt	LLR -14.71	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 49 kb · p 0.33 · regional, not allelic
Overall
CADD	27.5	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 0.0141% European (non-Finnish) · 166/1,179,436 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.0108% 174/1,612,924 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0141%	7,105
Remaining individualsnot grpmax-eligible	0.0112%	8,921
African / African-American	0.00134%	74,792

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.Cys259Phe
Coding: c.776G>T
MANE Select: NM_031900
Type: single nucleotide variant
Location: chr5:35026504 (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 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
AGXT2 p.Ala359Thr 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-cys259phe (accessed [today's date]).

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