Is AGT p.Ala74Val (c.221C>T) pathogenic?

AGT p.Ala74Val (c.221C>T) is classified Likely benign in AGT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely benign (0.0905); Ultra-rare (popmax 0.0666%, afr).

How common is AGT p.Ala74Val (c.221C>T) in the general population?

AGT p.Ala74Val (c.221C>T) is ultra-rare (popmax 0.0666%, afr) (gnomAD).

What do computational predictors say about AGT p.Ala74Val (c.221C>T)?

AlphaMissense predicts likely benign (score 0.0905) — an in-silico prediction, not a clinical call.

AGT p.Ala74Val

c.221C>T · rs140901725 · VCV2060625

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0905 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0666%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0905	likely benign
REVEL	0.202	benign-leaning
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -0.16, phastCons 0.003
Regional constraint	o/e 1.01	unconstrained · MANE · 7,679 bp · p 0.88 · regional, not allelic
Overall
CADD	12.1	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 A83V vs ClinVar A74V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0666% African / African-American · 50/75,080 alleles

Filtering AF 0.0519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0466%

Overall 0.00335% 54/1,614,272 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0666%	1,502
Remaining individualsnot grpmax-eligible	0.0032%	31,256
Admixed American	0.00167%	60,034
European (non-Finnish)	8.47e-05%	1,180,048

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.Ala74Val
Coding: c.221C>T
MANE Select: NM_001384479
dbSNP: rs140901725
Type: single nucleotide variant
Location: chr1:230710603 (GRCh38)
Gene constraint: LOEUF 1.202 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.74 · 22 PDB
Residue 74: a disulfide bond; an α-helix

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

Similar variants

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
AGT p.Arg366Leu 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-ala74val (accessed [today's date]).

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