# NM_014003.4(DHX38):c.498C>A (p.Arg166=)

https://sugi.bio/variant/dhx38-p-arg166

## Summary

**DHX38 p.Arg166= (c.498C>A)** is classified **Likely benign** in DHX38 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-12). Very rare (popmax 0.000254%, nfe).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the DHX38 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [DHX38](https://sugi.bio/atlas/gene/DHX38/) |
| Protein change (HGVS p.) | p.Arg166= |
| Coding change (HGVS c.) | c.498C>A |
| MANE Select transcript | [NM_014003](https://www.ncbi.nlm.nih.gov/nuccore/NM_014003) |
| Variant type | single nucleotide variant |
| Location | chr16:72096996-72096996 (GRCh38) |
| ClinVar | [VCV4775391](https://www.ncbi.nlm.nih.gov/clinvar/variation/4775391/) |

**All HGVS expressions:** `NC_000016.10:g.72096996C>A`, `NC_000016.9:g.72130895C>A`, `NG_034207.1:g.8281C>A`, `NM_014003.4:c.498C>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 (below), not from a missing predictor score.
- Conservation: phyloP 2.826, GERP 0.31, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 12.17**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.78 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,814 in the highest group · 3/1,461,430 alleles overall — very rare (popmax 0.000254%, nfe).

*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}

**DHX38** population constraint: LOEUF 0.752, pLI 2.7522e-20, missense-Z 2.3268. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **166** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 67.82, 16% of residues very-high.

**5 experimental structure(s)** (PDB): [5YZG](https://www.rcsb.org/structure/5YZG), [6ZYM](https://www.rcsb.org/structure/6ZYM), [7A5P](https://www.rcsb.org/structure/7A5P), [8I0W](https://www.rcsb.org/structure/8I0W), [9XTT](https://www.rcsb.org/structure/9XTT).

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

*Describes the biological roles of DHX38 (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:** DHX38's established molecular role includes RNA binding. p.Arg166= falls in the disordered region. In Reactome, DHX38 is annotated in disease pathway(s) including **Dengue Virus-Host Interactions**.

**Disease mechanism (Reactome):** DHX38 loss or alteration is curated in [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481).

### Pathways affected {#pathways}

DHX38 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| [Transport of Mature mRNA derived from an Intron-Containing Transcript](https://reactome.org/content/detail/R-HSA-159236) | curated |
| [mRNA 3'-end processing](https://reactome.org/content/detail/R-HSA-72187) | curated |
| [mRNA Splicing - Major Pathway](https://reactome.org/content/detail/R-HSA-72163) | curated |
| [RNA Polymerase II Transcription Termination](https://reactome.org/content/detail/R-HSA-73856) | other |

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

**Molecular function:** RNA binding.

**Biological process:** mRNA splicing, via spliceosome.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-12.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-12 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related DHX38 variant pages (same residue, condition, or type): [DHX38 p.Arg166Cys](/variant/dhx38-p-arg166cys), [DHX38 p.Arg166His](/variant/dhx38-p-arg166his), [DHX38 c.2011-3C>A](/variant/dhx38-c-2011-minus-3c-a), [DHX38 c.2262+3G>C](/variant/dhx38-c-2262-plus-3g-c), [DHX38 c.2262+4C>T](/variant/dhx38-c-2262-plus-4c-t), [DHX38 c.2262+5G>A](/variant/dhx38-c-2262-plus-5g-a), [DHX38 c.2964+3G>C](/variant/dhx38-c-2964-plus-3g-c), [DHX38 c.616+3A>G](/variant/dhx38-c-616-plus-3a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 4775391). 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.*