# NM_033124.5(DRC2):c.340G>C (p.Ala114Pro)

https://sugi.bio/variant/drc2-p-ala114pro

## Summary

**DRC2 p.Ala114Pro (c.340G>C)** is classified **Uncertain significance** in DRC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-08). AlphaMissense: likely pathogenic (0.8214); Ultra-rare (popmax 0.0147%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs543578641 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0147%, afr)

## For patients & families {#patients}

This is a change in the DRC2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [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.Ala114Pro |
| Coding change (HGVS c.) | c.340G>C |
| MANE Select transcript | [NM_033124](https://www.ncbi.nlm.nih.gov/nuccore/NM_033124) |
| dbSNP | [rs543578641](https://www.ncbi.nlm.nih.gov/snp/rs543578641/) |
| Variant type | single nucleotide variant |
| Location | chr12:48914443-48914443 (GRCh38) |
| ClinVar | [VCV2157433](https://www.ncbi.nlm.nih.gov/clinvar/variation/2157433/) |

**All HGVS expressions:** `NC_000012.11:g.49308226G>C`, `NC_000012.12:g.48914443G>C`, `NG_033837.1:g.15334G>C`, `NM_001286957.2:c.-90G>C`, `NM_033124.4:c.340G>C`, `NM_033124.5:c.340G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.8214)
- REVEL 0.173 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -11.801 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- Conservation: phyloP 6.656, GERP -0.604, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in DRC2 (of 2,864 modeled).
- CADD: **PHRED 19.88**. 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: **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 **0.0147%** (afr) · FAF95 0.00814% · FAF99 0.00632% · 11/75,034 in the highest group · 19/1,613,818 alleles overall — ultra-rare (popmax 0.0147%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0147% | 6,821 |
| Admixed American | 0.0117% | 8,571 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,478 |

*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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-08.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-08 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [primary ciliary dyskinesia 27](https://sugi.bio/atlas/disease/primary-ciliary-dyskinesia-27/).

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

## Similar variants {#similar}

Related DRC2 variant pages (same residue, condition, or type): [DRC2 p.Ala114Val](/variant/drc2-p-ala114val), [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.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 2026-10-11); 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 2157433). 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.*