Is AGT p.Arg449Cys (c.1345C>T) pathogenic?

AGT p.Arg449Cys (c.1345C>T) is classified Conflicting classifications of pathogenicity in AGT (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-02). AlphaMissense: likely benign (0.1025); Rare (popmax 0.222%, sas).

How common is AGT p.Arg449Cys (c.1345C>T) in the general population?

AGT p.Arg449Cys (c.1345C>T) is rare (popmax 0.222%, sas) (gnomAD).

What do computational predictors say about AGT p.Arg449Cys (c.1345C>T)?

AlphaMissense predicts likely benign (score 0.1025) — an in-silico prediction, not a clinical call.

AGT p.Arg449Cys

c.1345C>T · rs375261929 · VCV1125579

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1025 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.222%, sas)

Computational evidence

Protein change
AlphaMissense	0.1025	likely benign
REVEL	0.578	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.014	GERP -3.6, phastCons 0.001
Regional constraint	o/e 1.01	unconstrained · MANE · 7,679 bp · p 0.88 · regional, not allelic
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R458C vs ClinVar R449C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.222% South Asian · 202/91,092 alleles

Filtering AF 0.197% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.187%

Overall 0.0185% 298/1,614,198 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.222%	451
Middle Eastern	0.0661%	1,514
Remaining individualsnot grpmax-eligible	0.0336%	2,977
East Asian	0.0245%	4,079
African / African-American	0.00799%	12,508
European (non-Finnish)	0.00458%	21,853

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: AGT
Protein: p.Arg449Cys
Coding: c.1345C>T
MANE Select: NM_001384479
dbSNP: rs375261929
Type: single nucleotide variant
Location: chr1:230703227 (GRCh38)
Gene constraint: LOEUF 1.202 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.74 · 22 PDB

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

Similar variants

AGT p.Arg449His Uncertain significance ★ ⚠ same residue
AGT c.1060C>T Pathogenic/Likely pathogenic ★★ same type
AGT c.829+1G>T Pathogenic/Likely pathogenic ★★ same type
AGT c.1195G>A Uncertain significance ★★ ⚠ same type
AGT c.856G>T Uncertain significance ★★ ⚠ same type
AGT c.862C>T Uncertain significance ★★ ⚠ same type
AGT c.-17G>C Uncertain significance ★★ ⚠ same type
AGT p.Arg165Gln 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/agt-p-arg449cys (accessed [today's date]).

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