# NM_033124.5(DRC2):c.880C>T (p.Arg294Cys)

https://sugi.bio/variant/drc2-p-arg294cys

## Summary

**DRC2 p.Arg294Cys (c.880C>T)** is classified **Benign/Likely benign** in DRC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1103); Common (popmax 5.92%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with primary ciliary dyskinesia 27.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs78877829 · 5 submitters · 1 linked condition · AlphaMissense likely benign · common (popmax 5.92%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the DRC2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to primary ciliary dyskinesia 27.

*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 | DRC2 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/0015976/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DRC2](https://sugi.bio/atlas/gene/DRC2/) |
| Protein change (HGVS p.) | p.Arg294Cys |
| Coding change (HGVS c.) | c.880C>T |
| MANE Select transcript | [NM_033124](https://www.ncbi.nlm.nih.gov/nuccore/NM_033124) |
| dbSNP | [rs78877829](https://www.ncbi.nlm.nih.gov/snp/rs78877829/) |
| Variant type | single nucleotide variant |
| Location | chr12:48918757-48918757 (GRCh38) |
| ClinVar | [VCV262221](https://www.ncbi.nlm.nih.gov/clinvar/variation/262221/) |

**All HGVS expressions:** `NC_000012.11:g.49312540C>T`, `NC_000012.12:g.48918757C>T`, `NG_033837.1:g.19648C>T`, `NM_001286957.2:c.451C>T`, `NM_033124.5:c.880C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 5.92%, nfe) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.1103)
- REVEL 0.138 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.967 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.894, GERP 0.308, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.9**. 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 0.94** across the covering region of the MANE Select transcript (48,904,337–48,921,440), spanning 17,103 bp. Chi-square p 0.19. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.48 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 **5.92%** (nfe) · FAF95 5.88% · FAF99 5.87% · 69,844/1,179,950 in the highest group · 82,869/1,613,972 alleles overall — common (popmax 5.92%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 9.99% | 10 |
| European (non-Finnish) (grpmax) | 5.92% | 17 |
| Amish (not grpmax-eligible) | 5.7% | 18 |
| Remaining individuals (not grpmax-eligible) | 4.45% | 22 |
| Admixed American | 2.3% | 43 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.96% | 51 |
| South Asian | 1.2% | 83 |
| African / African-American | 0.91% | 110 |
| Middle Eastern | 0.562% | 178 |
| East Asian | 0.0668% | 1,496 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 27** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.21, 57% of residues very-high.

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

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** conflicting (4 Benign, 1 Likely benign).

**Submission history:** 5 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2019-08-24 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[primary ciliary dyskinesia 27](https://sugi.bio/atlas/disease/primary-ciliary-dyskinesia-27/).

**Reported phenotype names (ClinVar):** Primary ciliary dyskinesia 27, not specified, not provided, AllHighlyPenetrant, CILIARY DYSKINESIA, PRIMARY, 27, WITHOUT SITUS INVERSUS, none provided.

## Similar variants {#similar}

Related DRC2 variant pages (same residue, condition, or type): [DRC2 p.Arg294His](/variant/drc2-p-arg294his), [CCDC65 p.Arg70Gln](/variant/ccdc65-p-arg70gln), [CCDC65 p.Glu110Lys](/variant/ccdc65-p-glu110lys), [CCDC65 p.Lys158Asn](/variant/ccdc65-p-lys158asn), [DRC2 p.Ala109Val](/variant/drc2-p-ala109val), [DRC2 p.Ala114Pro](/variant/drc2-p-ala114pro), [DRC2 p.Arg118Cys](/variant/drc2-p-arg118cys), [DRC2 p.Arg315Gln](/variant/drc2-p-arg315gln).

### 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 262221). 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.*