Is AGO1 p.Pro227= (c.681A>G) pathogenic?

AGO1 p.Pro227= (c.681A>G) is classified Benign in AGO1 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2024-03-11). Common (popmax 69.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with AGO1-related disorder.

What condition is associated with AGO1 p.Pro227= (c.681A>G)?

AGO1 p.Pro227= (c.681A>G) is associated with AGO1-related disorder (ClinVar).

AGO1 p.Pro227=

Q: How common is AGO1 p.Pro227= (c.681A>G) in the general population?

AGO1 p.Pro227= (c.681A>G) is common (popmax 69.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.681A>G · rs2296470 · VCV3060004

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 69.7%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

AGO1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.25	GERP -5.8, phastCons 0.51
Overall
CADD	6.646	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 69.7% East Asian · 31,086/44,572 alleles

Filtering AF 69.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 68.8%

Overall 6.24% 98,077/1,571,186 alleles · common exomes 73,817/1,419,008 · genomes 24,260/152,178 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	69.7%	1
African / African-American	35.3%	3
Admixed American	32.5%	3
Remaining individualsnot grpmax-eligible	8.56%	12
South Asian	7.87%	13
Finnishnot grpmax-eligible	7.39%	14
Middle Eastern	2.47%	41
Ashkenazi Jewishnot grpmax-eligible	2.36%	42
European (non-Finnish)	0.587%	170

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: AGO1
Protein: p.Pro227=
Coding: c.681A>G
MANE Select: NM_012199
dbSNP: rs2296470
Type: single nucleotide variant
Location: chr1:35894068 (GRCh38)
Gene constraint: LOEUF 0.164 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 91.45 · 8 PDB
Residue 227: the paz domain

Full AGO1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

AGO1-related disorder

Similar variants

AGO1 c.650-2A>G Pathogenic ★ same condition
AGO1 p.Leu190Arg Pathogenic ★ same condition
AGO1 p.Cys749Tyr Uncertain significance ★ ⚠ same condition
AGO1 p.His166Tyr Uncertain significance ★ ⚠ same condition
AGO1 p.Thr781Met Conflicting classifications of pathogenicity ★ ⚠ same condition
AGO1 p.Asp595Ala Uncertain significance ⚠ same condition
AGO1 c.2265+4G>T Benign same condition
AGO1 p.Glu155= Likely benign same condition

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/ago1-p-pro227 (accessed [today's date]).

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