# NM_145038.5(DRC1):c.1509G>A (p.Ser503=)

https://sugi.bio/variant/drc1-p-ser503

## Summary

**DRC1 p.Ser503= (c.1509G>A)** is classified **Uncertain significance** in DRC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-23). Ultra-rare (popmax 0.012%, afr); Associated with primary ciliary dyskinesia.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · ultra-rare (popmax 0.012%, afr)

## For patients & families {#patients}

This is a change in the DRC1 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.

*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) |
| Clinical trials | 76 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DRC1 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/0004484/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DRC1](https://sugi.bio/atlas/gene/DRC1/) |
| Protein change (HGVS p.) | p.Ser503= |
| Coding change (HGVS c.) | c.1509G>A |
| MANE Select transcript | [NM_145038](https://www.ncbi.nlm.nih.gov/nuccore/NM_145038) |
| Variant type | single nucleotide variant |
| Location | chr2:26448803-26448803 (GRCh38) |
| ClinVar | [VCV4761720](https://www.ncbi.nlm.nih.gov/clinvar/variation/4761720/) |

**All HGVS expressions:** `NC_000002.11:g.26671671G>A`, `NC_000002.12:g.26448803G>A`, `NG_042824.1:g.51892G>A`, `NM_145038.5:c.1509G>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 0.84) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.477, GERP 1.74, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 26.8**. 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 **0.00**, donor loss **0.69**, acceptor gain **0.00**, donor gain **0.84**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.69**, acceptor gain **0.00**, donor gain **0.84**.
- Pangolin: Δ**0.81** (gain), gain 0.81 / loss 0.81. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.012%** (afr) · FAF95 0.00622% · FAF99 0.00467% · 9/75,062 in the highest group · 39/1,614,008 alleles overall — ultra-rare (popmax 0.012%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0328% | 3,048 |
| African / African-American (grpmax) | 0.012% | 8,340 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,246 |
| East Asian | 0.00223% | 44,884 |
| Admixed American | 0.00167% | 60,026 |
| South Asian | 0.0011% | 91,076 |
| European (non-Finnish) | 0.000339% | 295,001 |

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}

**DRC1** population constraint: LOEUF 0.867, pLI 1.5561e-18, missense-Z 0.65957. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **primary ciliary dyskinesia 21** — Definitive (AR)

## Protein context {#protein}

Residue **503** lies in a UniProt-annotated variant site (in cild21; multiple flagellar abnormalities are present in patient sperm); a UniProt-annotated variant site (in spgf80); a UniProt-annotated variant site (in cild21).

AlphaFold model confidence (whole protein): pLDDT 75.44, 34% of residues very-high.

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

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-23.

**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 | 2025-11-23 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Primary ciliary dyskinesia, Ciliary dyskinesia.

## Similar variants {#similar}

Related DRC1 variant pages (same residue, condition, or type): [DRC1 p.Ser503Leu](/variant/drc1-p-ser503leu), [DRC1 p.Gln118Ter](/variant/drc1-p-gln118ter), [DRC1 p.Gln337Ter](/variant/drc1-p-gln337ter), [DRC1 p.Ser642Ter](/variant/drc1-p-ser642ter), [DRC1 p.Ala250Val](/variant/drc1-p-ala250val), [DRC1 p.Ala391Val](/variant/drc1-p-ala391val), [DRC1 p.Ala416Gly](/variant/drc1-p-ala416gly), [DRC1 p.Ala45Val](/variant/drc1-p-ala45val).

### 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 4761720). 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.*