# NM_033124.5(DRC2):c.747G>A (p.Val249=)

https://sugi.bio/variant/drc2-p-val249

## Summary

**DRC2 p.Val249= (c.747G>A)** is classified **Benign** in DRC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-02). Very rare (popmax 0.00593%, nfe); Associated with primary ciliary dyskinesia 27.

**At a glance:** Benign · review: Single submitter · rsID rs201132346 · 1 submitter · 1 linked condition · very rare (popmax 0.00593%, nfe)

## For patients & families {#patients}

This is a change in the DRC2 gene that is classified as benign — not considered disease-causing, submitted by 1 submitter, 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.Val249= |
| Coding change (HGVS c.) | c.747G>A |
| MANE Select transcript | [NM_033124](https://www.ncbi.nlm.nih.gov/nuccore/NM_033124) |
| dbSNP | [rs201132346](https://www.ncbi.nlm.nih.gov/snp/rs201132346/) |
| Variant type | single nucleotide variant |
| Location | chr12:48918412-48918412 (GRCh38) |
| ClinVar | [VCV1170517](https://www.ncbi.nlm.nih.gov/clinvar/variation/1170517/) |

**All HGVS expressions:** `NC_000012.11:g.49312195G>A`, `NC_000012.12:g.48918412G>A`, `NG_033837.1:g.19303G>A`, `NM_001286957.2:c.318G>A`, `NM_033124.5:c.747G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.31) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.173, GERP -0.763, phastCons 0.788 — weakly conserved position
- CADD: **PHRED 13.22**. 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 **0.01**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.31**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.31**.
- Population frequency (gnomAD v4.1): grpmax **0.00593%** (nfe) · FAF95 0.00478% · FAF99 0.00439% · 70/1,180,036 in the highest group · 207/1,614,040 alleles overall — very rare (popmax 0.00593%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.203% | 492 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,415 |
| European (non-Finnish) (grpmax) | 0.00593% | 16,858 |
| East Asian | 0.00223% | 44,900 |

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** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-02.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-11-02 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Primary ciliary dyskinesia 27, CILIARY DYSKINESIA, PRIMARY, 27, WITHOUT SITUS INVERSUS.

## Similar variants {#similar}

Related DRC2 variant pages (same residue, condition, or type): [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.Arg294His](/variant/drc2-p-arg294his), [DRC2 p.Arg315Gln](/variant/drc2-p-arg315gln).

### 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 1170517). 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.*