# NM_001481.3(DRC4):c.1025G>C (p.Arg342Pro)

https://sugi.bio/variant/drc4-p-arg342pro

## Summary

**DRC4 p.Arg342Pro (c.1025G>C)** is classified **Uncertain significance** in DRC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-17). AlphaMissense: likely pathogenic (0.9648); Very rare (popmax 0.00178%, amr); Associated with primary ciliary dyskinesia 33.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs532241934 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00178%, amr)

## 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.Arg342Pro |
| Coding change (HGVS c.) | c.1025G>C |
| MANE Select transcript | [NM_001481](https://www.ncbi.nlm.nih.gov/nuccore/NM_001481) |
| dbSNP | [rs532241934](https://www.ncbi.nlm.nih.gov/snp/rs532241934/) |
| Variant type | single nucleotide variant |
| Location | chr16:90040313-90040313 (GRCh38) |
| ClinVar | [VCV1007085](https://www.ncbi.nlm.nih.gov/clinvar/variation/1007085/) |

**All HGVS expressions:** `NC_000016.10:g.90040313G>C`, `NC_000016.9:g.90106721G>C`, `NG_046598.1:g.25685G>C`, `NM_001286205.2:c.776G>C`, `NM_001286208.2:c.449G>C`, `NM_001286209.2:c.950G>C`, `NM_001481.3:c.1025G>C`, `NR_027335.2:n.797C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9648)
- REVEL 0.682 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.571 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.59, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in DRC4 (of 2,824 modeled).
- CADD: **PHRED 29.6**. 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 1.12** across the covering region of the MANE Select transcript (90,022,722–90,043,342), spanning 20,620 bp. Chi-square p 0.0024. 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 **0.00178%** (amr) · 1/56,316 in the highest group · 3/1,588,274 alleles overall — very rare (popmax 0.00178%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00178% | 56,316 |
| Remaining individuals (not grpmax-eligible) | 0.00163% | 61,480 |
| African / African-American | 0.00135% | 74,310 |

*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 **342** lies in 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 2020-02-17.

**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 | 2020-02-17 |

## 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.

## Similar variants {#similar}

Related DRC4 variant pages (same residue, condition, or type): [DRC4 p.Arg342Trp](/variant/drc4-p-arg342trp), [DRC4 p.Arg342=](/variant/drc4-p-arg342), [DRC4 p.Arg342Gln](/variant/drc4-p-arg342gln), [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).

### 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 1007085). 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.*