# NM_016222.4(DDX41):c.963G>A (p.Pro321=)

https://sugi.bio/variant/ddx41-p-pro321

## Summary

**DDX41 p.Pro321= (c.963G>A)** is classified **Conflicting classifications of pathogenicity** in DDX41 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-10). Very rare (popmax 0.00801%, afr); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs200664784 · 3 submitters · 2 linked conditions · very rare (popmax 0.00801%, afr)

## For patients & families {#patients}

This is a change in the DDX41 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DDX41](https://sugi.bio/atlas/gene/DDX41/) |
| Protein change (HGVS p.) | p.Pro321= |
| Coding change (HGVS c.) | c.963G>A |
| MANE Select transcript | [NM_016222](https://www.ncbi.nlm.nih.gov/nuccore/NM_016222) |
| dbSNP | [rs200664784](https://www.ncbi.nlm.nih.gov/snp/rs200664784/) |
| Variant type | single nucleotide variant |
| Location | chr5:177513820-177513820 (GRCh38) |
| ClinVar | [VCV2674770](https://www.ncbi.nlm.nih.gov/clinvar/variation/2674770/) |

**All HGVS expressions:** `LRG_1386:g.8142G>A`, `LRG_1386t1:c.963G>A`, `NC_000005.10:g.177513820C>T`, `NC_000005.9:g.176940821C>T`, `NG_046846.2:g.8142G>A`, `NM_001321732.2:c.585G>A`, `NM_001321830.2:c.585G>A`, `NM_016222.2:c.963G>A`, `NM_016222.4:c.963G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.45) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.224, GERP -4.79, phastCons 0.002 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 17.89**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.09**, donor loss **0.00**, acceptor gain **0.45**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.45**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00801%** (afr) · FAF95 0.00347% · FAF99 0.00229% · 6/74,902 in the highest group · 47/1,613,532 alleles overall — very rare (popmax 0.00801%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00801% | 12,484 |
| East Asian | 0.00446% | 22,446 |
| European (non-Finnish) | 0.00297% | 33,714 |
| South Asian | 0.0022% | 45,542 |
| Admixed American | 0.00167% | 59,998 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,472 |

*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}

**DDX41** population constraint: LOEUF 0.768, pLI 8.2138e-10, missense-Z 3.1508; 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):

- **DDX41-related hematologic malignancy predisposition syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **321** lies in the helicase atp-binding domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 78.38, 39% of residues very-high.

**5 experimental structure(s)** (PDB): [2P6N](https://www.rcsb.org/structure/2P6N), [5GVR](https://www.rcsb.org/structure/5GVR), [5GVS](https://www.rcsb.org/structure/5GVS), [5H1Y](https://www.rcsb.org/structure/5H1Y), [8C6J](https://www.rcsb.org/structure/8C6J).

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

*Describes the biological roles of DDX41 (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:** DDX41's established molecular role includes RNA binding. p.Pro321= falls in the helicase atp-binding domain.


### Pathways affected {#pathways}

DDX41 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [IRF3-mediated induction of type I IFN](https://reactome.org/content/detail/R-HSA-3270619) | curated |
| [Regulation of innate immune responses to cytosolic DNA](https://reactome.org/content/detail/R-HSA-3134975) | curated |
| [STING mediated induction of host immune responses](https://reactome.org/content/detail/R-HSA-1834941) | curated |
| [mRNA Splicing - Major Pathway](https://reactome.org/content/detail/R-HSA-72163) | curated |

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

**Molecular function:** RNA binding, RNA helicase activity.

**Biological process:** mRNA splicing, via spliceosome, cell population proliferation, cell differentiation, cGAS/STING signaling pathway.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-02-10.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-09-27 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-02-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-15 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [DDX41-related hematologic malignancy predisposition syndrome](https://sugi.bio/atlas/disease/ddx41-related-hematologic-malignancy-predisposition-syndrome/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, DDX41-related hematologic malignancy predisposition syndrome, not provided, Myeloproliferative/lymphoproliferative neoplasms, familial (multiple types), susceptibility to, DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia, none provided.

## Similar variants {#similar}

Related DDX41 variant pages (same residue, condition, or type): [DDX41 p.Pro321Gln](/variant/ddx41-p-pro321gln), [DDX41 p.Pro321Leu](/variant/ddx41-p-pro321leu), [DDX41 c.1303-2A>G](/variant/ddx41-c-1303-minus-2a-g), [DDX41 c.27+1G>A](/variant/ddx41-c-27-plus-1g-a), [DDX41 c.434+1G>A](/variant/ddx41-c-434-plus-1g-a), [DDX41 c.434+1G>C](/variant/ddx41-c-434-plus-1g-c), [DDX41 c.571+1G>A](/variant/ddx41-c-571-plus-1g-a), [DDX41 c.572-1G>A](/variant/ddx41-c-572-minus-1g-a).

### 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 2674770). 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.*