Is AGXT2 p.Arg133Cys (c.397C>T) pathogenic?

AGXT2 p.Arg133Cys (c.397C>T) is classified Benign in AGXT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-03-29). AlphaMissense: likely benign (0.08); Low-frequency (popmax 2.83%, afr).

How common is AGXT2 p.Arg133Cys (c.397C>T) in the general population?

AGXT2 p.Arg133Cys (c.397C>T) is low-frequency (popmax 2.83%, afr) (gnomAD).

What do computational predictors say about AGXT2 p.Arg133Cys (c.397C>T)?

AlphaMissense predicts likely benign (score 0.08) — an in-silico prediction, not a clinical call.

AGXT2 p.Arg133Cys

c.397C>T · rs140156063 · VCV789736

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.08 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.83%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.08	likely benign
REVEL	0.392	indeterminate
SaProt	LLR -8.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.62, phastCons 0.87
Regional constraint	o/e 1.04	unconstrained · MANE · 49 kb · p 0.33 · regional, not allelic
Overall
CADD	22.1	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 2.83% African / African-American · 2,123/75,052 alleles

Filtering AF 2.73% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.69%

Overall 0.15% 2,426/1,614,140 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.83%	35
Remaining individualsnot grpmax-eligible	0.192%	521
Admixed American	0.192%	522
Middle Eastern	0.166%	604
South Asian	0.0121%	8,280
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,801
European (non-Finnish)	0.00373%	26,818
East Asian	0.00223%	44,872

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.Arg133Cys
Coding: c.397C>T
MANE Select: NM_031900
dbSNP: rs140156063
Type: single nucleotide variant
Location: chr5:35037031 (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.Arg133His Benign ★ same residue
AGXT2 c.1188+1G>A Benign/Likely 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-arg133cys (accessed [today's date]).

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