# NM_033124.5(DRC2):c.494del (p.Glu165fs)

https://sugi.bio/variant/drc2-p-glu165fs

## Summary

**DRC2 p.Glu165fs (c.494del)** is classified **Pathogenic** in DRC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-11-19). Very rare (popmax 0.000254%, nfe); Associated with primary ciliary dyskinesia 27.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1555174708 · 2 submitters · 1 linked condition · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the DRC2 gene that is considered disease-causing, submitted by 2 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.Glu165fs |
| Coding change (HGVS c.) | c.494del |
| MANE Select transcript | [NM_033124](https://www.ncbi.nlm.nih.gov/nuccore/NM_033124) |
| dbSNP | [rs1555174708](https://www.ncbi.nlm.nih.gov/snp/rs1555174708/) |
| Variant type | Deletion |
| Location | chr12:48916993-48916993 (GRCh38) |
| ClinVar | [VCV474640](https://www.ncbi.nlm.nih.gov/clinvar/variation/474640/) |

**All HGVS expressions:** `NC_000012.11:g.49310776del`, `NC_000012.12:g.48916993del`, `NG_033837.1:g.17884del`, `NM_001286957.2:c.65del`, `NM_033124.5:c.494del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 9.942, GERP 1.86, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 8**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,932 in the highest group · 3/1,461,748 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}


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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-11-19.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2017–2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Center for Personalized Medicine, Children's Hospital Los Angeles | Pathogenic | criteria provided, single submitter | clinical testing | 2018-11-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2017-04-06 |

## 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 provided, CILIARY DYSKINESIA, PRIMARY, 27, WITHOUT SITUS INVERSUS, none provided.

## Similar variants {#similar}

Related DRC2 variant pages (same residue, condition, or type): [DRC2 c.1026+8_1026+9del](/variant/drc2-c-1026-plus-8-1026-plus-9del), [DRC2 p.Asn232_Tyr233insTer](/variant/drc2-p-asn232-tyr233inster), [DRC2 p.Leu247fs](/variant/drc2-p-leu247fs), [DRC2 p.Val302fs](/variant/drc2-p-val302fs), [DRC2 p.Val323fs](/variant/drc2-p-val323fs), [CCDC65 p.Phe457fs](/variant/ccdc65-p-phe457fs), [DRC2 p.Lys49_Ala55del](/variant/drc2-p-lys49-ala55del), [DRC2 c.1179+14del](/variant/drc2-c-1179-plus-14del).

### 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 474640). 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.*