Is AGO2 p.Arg714Trp (c.2140C>T) pathogenic?

AGO2 p.Arg714Trp (c.2140C>T) is classified Pathogenic/Likely pathogenic in AGO2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-20). AlphaMissense: likely pathogenic (0.9986); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder.

What condition is associated with AGO2 p.Arg714Trp (c.2140C>T)?

AGO2 p.Arg714Trp (c.2140C>T) is associated with neurodevelopmental disorder (ClinVar).

How common is AGO2 p.Arg714Trp (c.2140C>T) in the general population?

AGO2 p.Arg714Trp (c.2140C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AGO2 p.Arg714Trp (c.2140C>T)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

AGO2 p.Arg714Trp

c.2140C>T · rs866981753 · VCV1316034

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic ✓ concordant with ClinVar · top 8% in AGO2
REVEL	0.675	pathogenic-leaning
SaProt	LLR -15.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -3.1, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 25 kb · p 1.2e-55 · regional, not allelic
Overall
CADD	24.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AGO2
Protein: p.Arg714Trp
Coding: c.2140C>T
MANE Select: NM_012154
dbSNP: rs866981753
Type: single nucleotide variant
Location: chr8:140539349 (GRCh38)
Gene constraint: LOEUF 0.102 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 92.82 · 71 PDB
Residue 714: the piwi domain

Full AGO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AGO2 p.Cys751Tyr Pathogenic/Likely pathogenic ★★ same type
AGO2 p.Gly201Val Pathogenic/Likely pathogenic ★★ same type
AGO2 p.Gly604Arg Pathogenic/Likely pathogenic ★★ same type
AGO2 p.Thr357Met Pathogenic/Likely pathogenic ★★ same type
AGO2 p.Ala142Thr Uncertain significance ★★ ⚠ same type
AGO2 p.Ala372Val Uncertain significance ★★ ⚠ same type
AGO2 p.Arg630His Uncertain significance ★★ ⚠ same type
AGO2 p.Asp89Glu 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/ago2-p-arg714trp (accessed [today's date]).

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