Is AGO4 p.Pro16Ala (c.46C>G) pathogenic?

AGO4 p.Pro16Ala (c.46C>G) is classified Uncertain significance in AGO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-24). AlphaMissense: ambiguous (0.3469); Very rare (popmax 0.00167%, amr).

How common is AGO4 p.Pro16Ala (c.46C>G) in the general population?

AGO4 p.Pro16Ala (c.46C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about AGO4 p.Pro16Ala (c.46C>G)?

AlphaMissense predicts ambiguous (score 0.3469) — an in-silico prediction, not a clinical call.

AGO4 p.Pro16Ala

c.46C>G · rs772782939 · VCV2478355

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3469 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.3469	ambiguous
REVEL	0.302	indeterminate
SaProt	LLR -7.75	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 23 kb · p 6.7e-06 · regional, not allelic
Overall
CADD	24.2	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 0.00167% Admixed American · 1/59,948 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000806% 13/1,613,078 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,948
European (non-Finnish)	0.00102%	98,297

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: AGO4
Protein: p.Pro16Ala
Coding: c.46C>G
MANE Select: NM_017629
dbSNP: rs772782939
Type: single nucleotide variant
Location: chr1:35816908 (GRCh38)
Gene constraint: LOEUF 0.393 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.56 · 1 PDB
Residue 16: an α-helix

Full AGO4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AGO4 p.Pro16Leu Uncertain significance ★ ⚠ same residue
AGO4 p.Arg277Trp Uncertain significance ★★ ⚠ same type
AGO4 p.Ala293Pro Uncertain significance ★ ⚠ same type
AGO4 p.Ala449Val Uncertain significance ★ ⚠ same type
AGO4 p.Arg100Gln Uncertain significance ★ ⚠ same type
AGO4 p.Arg100Gly Uncertain significance ★ ⚠ same type
AGO4 p.Arg17Cys Uncertain significance ★ ⚠ same type
AGO4 p.Arg18Cys 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/ago4-p-pro16ala (accessed [today's date]).

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