Is DICER1 p.Arg385Ser (c.1153C>A) pathogenic?

DICER1 p.Arg385Ser (c.1153C>A) is classified Uncertain significance in DICER1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-19). AlphaMissense: ambiguous (0.4271); Very rare (popmax 0.0011%, sas); Associated with DICER1-related tumor predisposition.

What condition is associated with DICER1 p.Arg385Ser (c.1153C>A)?

DICER1 p.Arg385Ser (c.1153C>A) is associated with DICER1-related tumor predisposition, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, pleuropulmonary blastoma (ClinVar).

How common is DICER1 p.Arg385Ser (c.1153C>A) in the general population?

DICER1 p.Arg385Ser (c.1153C>A) is very rare (popmax 0.0011%, sas) (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.Arg385Ser (c.1153C>A)?

AlphaMissense predicts ambiguous (score 0.4271) — an in-silico prediction, not a clinical call.

DICER1 p.Arg385Ser

c.1153C>A · rs746886465 · VCV646219

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4271 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

DICER1-related tumor predisposition

Computational evidence

Protein change
AlphaMissense	0.4271	ambiguous
REVEL	0.25	benign-leaning
SaProt	LLR -10.43	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 25 kb · p 4.8e-17 · regional, not allelic
Overall
CADD	25.1	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 0.0011% South Asian · 1/91,078 alleles

Overall 6.84e-05% 1/1,461,806 alleles · very rare

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.Arg385Ser
Coding: c.1153C>A
MANE Select: NM_177438
dbSNP: rs746886465
Type: single nucleotide variant
Location: chr14:95124419 (GRCh38)
Gene constraint: LOEUF 0.275 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 67.89 · 21 PDB
Residue 385: an α-helix; 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: goiter, multinodular 1, with or without Sertoli-Leydig cell tumors pleuropulmonary blastoma global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome rhabdomyosarcoma, embryonal, 2

For DICER1 tumor-predisposition syndrome (Orphanet):

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

Similar variants

DICER1 p.Arg385Cys Uncertain significance ★★ ⚠ same residue
DICER1 p.Arg385Gly Uncertain significance ★★ ⚠ same residue
DICER1 p.Arg385His Uncertain significance ★★ ⚠ same residue
DICER1 p.Arg385fs Likely pathogenic ★ same residue
DICER1 p.Arg385Leu Uncertain significance ★ ⚠ same residue
DICER1 p.Arg385= Likely benign ★ same residue
DICER1 c.1509+16A>G Likely pathogenic ★★★ same condition
DICER1 c.1752+213A>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-arg385ser (accessed [today's date]).

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