Is DICER1 p.Ile1663Met (c.4989A>G) pathogenic?

DICER1 p.Ile1663Met (c.4989A>G) is classified Uncertain significance in DICER1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-25). AlphaMissense: likely benign (0.2491); Very rare (popmax 0.00167%, amr); Associated with DICER1-related tumor predisposition.

What condition is associated with DICER1 p.Ile1663Met (c.4989A>G)?

DICER1 p.Ile1663Met (c.4989A>G) is associated with DICER1-related tumor predisposition, hereditary neoplastic syndrome (ClinVar).

How common is DICER1 p.Ile1663Met (c.4989A>G) in the general population?

DICER1 p.Ile1663Met (c.4989A>G) is very rare (popmax 0.00167%, amr) (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.Ile1663Met (c.4989A>G)?

AlphaMissense predicts likely benign (score 0.2491) — an in-silico prediction, not a clinical call.

DICER1 p.Ile1663Met

c.4989A>G · rs1253443798 · VCV842723

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2491 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

DICER1-related tumor predisposition

Computational evidence

Protein change
AlphaMissense	0.2491	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -4.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.29	GERP -3.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 337 bp · p 0.39 · regional, not allelic
Overall
CADD	19.64	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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 · 1/60,026 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,880 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,026
European (non-Finnish)	0.000169%	590,005

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: DICER1
Protein: p.Ile1663Met
Coding: c.4989A>G
MANE Select: NM_177438
dbSNP: rs1253443798
Type: single nucleotide variant
Location: chr14:95095931 (GRCh38)
Gene constraint: LOEUF 0.275 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 67.89 · 21 PDB
Residue 1663: a turn

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.Ile1663Thr Uncertain significance ★★ ⚠ same residue
DICER1 p.Ile1663Val Uncertain significance ★★ ⚠ same residue
DICER1 p.Ile1663Leu Uncertain significance ★ ⚠ same residue
DICER1 p.Ile1663= Likely benign ★ same residue
DICER1 p.Ile1663fs Pathogenic ★★ 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

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-ile1663met (accessed [today's date]).

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