# NM_001481.3(DRC4):c.549A>T (p.Arg183=)

https://sugi.bio/variant/drc4-p-arg183

## Summary

**DRC4 p.Arg183= (c.549A>T)** is classified **Uncertain significance** in DRC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-26). Very rare (popmax 8.47e-05%, nfe); Associated with primary ciliary dyskinesia 33.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2036831256 · 1 submitter · 1 linked condition · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the DRC4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to primary ciliary dyskinesia 33.

*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, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Neonatal |
| Prevalence | 1-5 / 10 000 (Pakistan) |
| Diagnostic panels | DRC4 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Primary ciliary dyskinesia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Chronic otitis media — Frequent (79-30%)
- Recurrent otitis media — Frequent (79-30%)
- Nasal congestion — Frequent (79-30%)
- Chronic rhinitis — Frequent (79-30%)
- Neonatal respiratory distress — Frequent (79-30%)
- Male infertility — Frequent (79-30%)
- Recurrent sinopulmonary infections — Frequent (79-30%)
- Chronic sinusitis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016154/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DRC4](https://sugi.bio/atlas/gene/DRC4/) |
| Protein change (HGVS p.) | p.Arg183= |
| Coding change (HGVS c.) | c.549A>T |
| MANE Select transcript | [NM_001481](https://www.ncbi.nlm.nih.gov/nuccore/NM_001481) |
| dbSNP | [rs2036831256](https://www.ncbi.nlm.nih.gov/snp/rs2036831256/) |
| Variant type | single nucleotide variant |
| Location | chr16:90035686-90035686 (GRCh38) |
| ClinVar | [VCV1911077](https://www.ncbi.nlm.nih.gov/clinvar/variation/1911077/) |

**All HGVS expressions:** `NC_000016.10:g.90035686A>T`, `NC_000016.9:g.90102094A>T`, `NG_046598.1:g.21058A>T`, `NM_001286205.2:c.300A>T`, `NM_001286208.2:c.-26-695A>T`, `NM_001286209.2:c.474A>T`, `NM_001481.3:c.549A>T`

## 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 **donor loss** (Δ 0.79) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.276, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 19.58**. 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 **0.05**, donor loss **0.79**, acceptor gain **0.00**, donor gain **0.09**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.79**, acceptor gain **0.00**, donor gain **0.09**.
- Pangolin: Δ**0.64** (loss), gain 0.19 / loss 0.64. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,026 in the highest group · 1/1,614,168 alleles overall — very rare (popmax 8.47e-05%, 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}


Curated gene–disease validity (ClinGen):

- **primary ciliary dyskinesia 33** — Definitive (AR)

## Protein context {#protein}

Residue **183** lies in the 'microtubule-binding' region; a UniProt-annotated variant site (in cild33; loss of localization to cilia; abnormal cilia with axonemal disorganization).

AlphaFold model confidence (whole protein): pLDDT 85.12, 60% of residues very-high.

**1 experimental structure(s)** (PDB): [8J07](https://www.rcsb.org/structure/8J07).

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

*Describes the biological roles of DRC4 (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.*


### Pathways affected {#pathways}

DRC4 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of SMO](https://reactome.org/content/detail/R-HSA-5635838) | curated |

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

**Biological process:** axoneme assembly, cilium movement involved in cell motility, protein localization to cilium, positive regulation of protein localization to cilium.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-26.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-26 |

## Associated conditions {#conditions}

[primary ciliary dyskinesia 33](https://sugi.bio/atlas/disease/primary-ciliary-dyskinesia-33/).

**Reported phenotype names (ClinVar):** Primary ciliary dyskinesia 33, CILIARY DYSKINESIA, PRIMARY, 33, WITHOUT SITUS INVERSUS.

## Same-residue context {#hotspot}

Residue **183** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DRC4 p.Arg183Ter](/variant/drc4-p-arg183ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DRC4 variant pages (same residue, condition, or type): [DRC4 p.Arg183Ter](/variant/drc4-p-arg183ter), [DRC4 c.495+1G>T](/variant/drc4-c-495-plus-1g-t), [DRC4 p.Gln357Ter](/variant/drc4-p-gln357ter), [DRC4 p.Ala280Thr](/variant/drc4-p-ala280thr), [DRC4 p.Ala460Pro](/variant/drc4-p-ala460pro), [DRC4 p.Arg143Trp](/variant/drc4-p-arg143trp), [DRC4 p.Arg164Trp](/variant/drc4-p-arg164trp), [DRC4 p.Arg203Gln](/variant/drc4-p-arg203gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1911077). 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.*