Is DICER1 p.Arg490Pro (c.1469G>C) pathogenic?

DICER1 p.Arg490Pro (c.1469G>C) is classified Uncertain significance in DICER1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-10). AlphaMissense: likely pathogenic (0.8118); Absent from gnomAD v4.1; Associated with DICER1-related tumor predisposition.

What condition is associated with DICER1 p.Arg490Pro (c.1469G>C)?

DICER1 p.Arg490Pro (c.1469G>C) is associated with DICER1-related tumor predisposition, hereditary neoplastic syndrome (ClinVar).

How common is DICER1 p.Arg490Pro (c.1469G>C) in the general population?

DICER1 p.Arg490Pro (c.1469G>C) is absent from gnomAD v4.1 (gnomAD).

How is DICER1 tumor-predisposition syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DICER1 p.Arg490Pro (c.1469G>C)?

AlphaMissense predicts likely pathogenic (score 0.8118) — an in-silico prediction, not a clinical call.

DICER1 p.Arg490Pro

c.1469G>C · rs1006363970 · VCV1056117

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8118 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

DICER1-related tumor predisposition

Computational evidence

Protein change
AlphaMissense	0.8118	likely pathogenic
REVEL	0.453	indeterminate
SaProt	LLR -7.81	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.66, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 25 kb · p 4.8e-17 · regional, not allelic
Overall
CADD	28.6	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: DICER1
Protein: p.Arg490Pro
Coding: c.1469G>C
MANE Select: NM_177438
dbSNP: rs1006363970
Type: single nucleotide variant
Location: chr14:95117662 (GRCh38)
Gene constraint: LOEUF 0.275 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 67.89 · 21 PDB
Residue 490: the helicase c-terminal domain; the 'required for interaction with prkra and tarbp2' region

Full DICER1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hereditary neoplastic syndrome

For DICER1 tumor-predisposition syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

DICER1 p.Arg490His Uncertain significance ★★ ⚠ same residue
DICER1 p.Arg490Ser Uncertain significance ★★ ⚠ same residue
DICER1 p.Arg490= Likely benign ★★ same residue
DICER1 p.Arg490Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
DICER1 c.1509+16A>G Likely pathogenic ★★★ same condition
DICER1 c.1752+213A>G Likely pathogenic ★★★ same condition
DICER1 c.1753-9A>G Likely pathogenic ★★★ same condition
DICER1 c.1907+1G>A Pathogenic ★★★ 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/dicer1-p-arg490pro (accessed [today's date]).

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