# NM_177438.3(DICER1):c.4989A>G (p.Ile1663Met)

https://sugi.bio/variant/dicer1-p-ile1663met

## Summary

**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.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1253443798 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the DICER1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to DICER1-related tumor predisposition.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DICER1 is a diagnostic-grade gene on 9 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010734/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DICER1](https://sugi.bio/atlas/gene/DICER1/) |
| Protein change (HGVS p.) | p.Ile1663Met |
| Coding change (HGVS c.) | c.4989A>G |
| MANE Select transcript | [NM_177438](https://www.ncbi.nlm.nih.gov/nuccore/NM_177438) |
| dbSNP | [rs1253443798](https://www.ncbi.nlm.nih.gov/snp/rs1253443798/) |
| Variant type | single nucleotide variant |
| Location | chr14:95095931-95095931 (GRCh38) |
| ClinVar | [VCV842723](https://www.ncbi.nlm.nih.gov/clinvar/variation/842723/) |

**All HGVS expressions:** `LRG_492:g.66492A>G`, `LRG_492t1:c.4989A>G`, `NC_000014.8:g.95562268T>C`, `NC_000014.9:g.95095931T>C`, `NG_016311.1:g.66492A>G`, `NM_001195573.1:c.4989A>G`, `NM_001271282.3:c.4989A>G`, `NM_001291628.2:c.4989A>G`, `NM_030621.4:c.4989A>G`, `NM_177438.3:c.4989A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2491)
- REVEL 0.425 (indeterminate)
- SaProt LLR -4.724 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 0.288, GERP -3.48, phastCons 0.996 — weakly conserved position
- CADD: **PHRED 19.64**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.93** across the covering region of the MANE Select transcript (95,095,874–95,096,211), spanning 337 bp. Chi-square p 0.39. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/60,026 in the highest group · 3/1,461,880 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 60,026 |
| European (non-Finnish) | 0.000169% | 590,005 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DICER1** population constraint: LOEUF 0.275, pLI 1, missense-Z 6.1513; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **DICER1-related tumor predisposition** — Definitive (AD)

## Protein context {#protein}

Residue **1663** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 67.89, 17% of residues very-high.

**21 experimental structure(s)** (PDB): [21CB](https://www.rcsb.org/structure/21CB), [21CN](https://www.rcsb.org/structure/21CN), [21CQ](https://www.rcsb.org/structure/21CQ), [2EB1](https://www.rcsb.org/structure/2EB1), [4NGB](https://www.rcsb.org/structure/4NGB), [4NGC](https://www.rcsb.org/structure/4NGC).

## What this gene does {#gene-function}

*Describes the biological roles of DICER1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** DICER1's established molecular role includes double-stranded RNA binding.


### Pathways affected {#pathways}

DICER1 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [MicroRNA (miRNA) biogenesis](https://reactome.org/content/detail/R-HSA-203927) | curated |
| [Regulation of MITF-M-dependent genes involved in apoptosis](https://reactome.org/content/detail/R-HSA-9824594) | curated |
| [Small interfering RNA (siRNA) biogenesis](https://reactome.org/content/detail/R-HSA-426486) | curated |
| [M-decay: degradation of maternal mRNAs by maternally stored factors](https://reactome.org/content/detail/R-HSA-9820841) | electronic |
| [tRNA-derived small RNA (tsRNA or tRNA-related fragment, tRF) biogenesis](https://reactome.org/content/detail/R-HSA-9708296) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** double-stranded RNA binding, RNA endonuclease activity, ribonuclease III activity, protein domain specific binding, siRNA binding, pre-miRNA binding.

**Biological process:** negative regulation of gene expression, negative regulation of tumor necrosis factor-mediated signaling pathway, siRNA processing, pre-miRNA processing, negative regulation of tumor necrosis factor production, miRNA processing.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-25.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-25 |

## Associated conditions {#conditions}

[DICER1-related tumor predisposition](https://sugi.bio/atlas/disease/dicer1-related-tumor-predisposition/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** DICER1-related tumor predisposition, Hereditary cancer-predisposing syndrome, DICER1 syndrome, DICER1-related pleuropulmonary blastoma cancer predisposition syndrome, Neoplastic Syndromes, Hereditary, Hereditary neoplastic syndrome, Tumor predisposition, Hereditary Cancer Syndrome.

## Same-residue context {#hotspot}

Residue **1663** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DICER1 p.Ile1663fs](/variant/dicer1-p-ile1663fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DICER1 variant pages (same residue, condition, or type): [DICER1 p.Ile1663Thr](/variant/dicer1-p-ile1663thr), [DICER1 p.Ile1663Val](/variant/dicer1-p-ile1663val), [DICER1 p.Ile1663Leu](/variant/dicer1-p-ile1663leu), [DICER1 p.Ile1663=](/variant/dicer1-p-ile1663), [DICER1 p.Ile1663fs](/variant/dicer1-p-ile1663fs), [DICER1 c.1509+16A>G](/variant/dicer1-c-1509-plus-16a-g), [DICER1 c.1752+213A>G](/variant/dicer1-c-1752-plus-213a-g), [DICER1 c.1753-9A>G](/variant/dicer1-c-1753-minus-9a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 842723). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*