# NM_001369.3(DNAH5):c.10815del (p.Pro3606fs)

https://sugi.bio/variant/dnah5-p-pro3606fs

## Summary

**DNAH5 p.Pro3606fs (c.10815del)** is classified **Pathogenic** in DNAH5 (ClinVar, Multiple submitters, 28 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0541%, nfe); Associated with DNAH5-related disorders.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs397515540 · 28 submitters · 3 linked conditions · ultra-rare (popmax 0.0541%, nfe)

## For patients & families {#patients}

This is a change in the DNAH5 gene that is considered disease-causing, submitted by 28 submitters, and is linked to DNAH5-related disorders.

*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 | [DNAH5](https://sugi.bio/atlas/gene/DNAH5/) |
| Protein change (HGVS p.) | p.Pro3606fs |
| Coding change (HGVS c.) | c.10815del |
| MANE Select transcript | [NM_001369](https://www.ncbi.nlm.nih.gov/nuccore/NM_001369) |
| dbSNP | [rs397515540](https://www.ncbi.nlm.nih.gov/snp/rs397515540/) |
| Variant type | Deletion |
| Location | chr5:13753290-13753290 (GRCh38) |
| ClinVar | [VCV65636](https://www.ncbi.nlm.nih.gov/clinvar/variation/65636/) |

**All HGVS expressions:** `NC_000005.10:g.13753290del`, `NC_000005.9:g.13753399del`, `NG_013081.2:g.196191del`, `NM_001369.2:c.10815delT`, `NM_001369.3:c.10815del`, `NM_001369.3:c.10815delT`

## 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 11.859, GERP 2.76, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.764, pLI 8.8294e-79. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 63 of 79**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 24.8**. 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: **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 **0.0541%** (nfe) · FAF95 0.0506% · FAF99 0.0492% · 638/1,179,900 in the highest group · 664/1,613,778 alleles overall — ultra-rare (popmax 0.0541%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0541% | 1,849 |
| Remaining individuals (not grpmax-eligible) | 0.032% | 3,124 |
| Finnish (not grpmax-eligible) | 0.00469% | 21,341 |
| African / African-American | 0.00401% | 24,963 |

*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}

**DNAH5** population constraint: LOEUF 0.764, pLI 8.8294e-79, missense-Z 2.1186; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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 3** — Definitive (AR)

## Protein context {#protein}

Residue **3606** lies in the 'aaa 5' region.

**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 2025-12-23.

**Submitter consensus:** conflicting (25 Pathogenic, 2 Likely pathogenic, 1 not provided).

**Submission history:** 28 submissions (2006–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-20 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2017-01-03 |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Pathogenic | criteria provided, single submitter | clinical testing | 2019-11-27 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2006-07-15 |
| Yale Center for Mendelian Genomics, Yale University | Likely pathogenic | no assertion criteria provided | literature only | 2018-08-01 |
| GeneReviews | not provided | no classification provided | literature only |  |
| Genetics and Molecular Pathology, SA Pathology | Pathogenic | criteria provided, single submitter | clinical testing | 2020-05-13 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-03 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-08 |
| Illumina Laboratory Services, Illumina | Pathogenic | criteria provided, single submitter | clinical testing | 2016-10-17 |
| Centre for Genomic and Experimental Medicine, University of Edinburgh | Pathogenic | criteria provided, single submitter | research | 2020-04-01 |
| HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Pathogenic | criteria provided, single submitter | research | 2020-03-26 |
| Genomics England Pilot Project, Genomics England | Likely pathogenic | no assertion criteria provided | clinical testing |  |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-02 |
| Johns Hopkins Genomics, Johns Hopkins University | Pathogenic | criteria provided, single submitter | clinical testing | 2022-12-06 |
| Molecular Genetics, Royal Melbourne Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-05 |
| Clinical Genetics Laboratory, Skane University Hospital Lund | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-27 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-23 |
| Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-11 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Laboratory of Genetics, Children's Clinical University Hospital Latvia | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-16 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2020-02-19 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-01 |
| Variantyx, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-11 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-23 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-09 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2021-10-01 |

## Associated conditions {#conditions}

[DNAH5-related disorders](https://sugi.bio/atlas/disease/dnah5-related-disorders/), [primary ciliary dyskinesia 3](https://sugi.bio/atlas/disease/primary-ciliary-dyskinesia-3/), [primary ciliary dyskinesia](https://sugi.bio/atlas/disease/primary-ciliary-dyskinesia/).

**Reported phenotype names (ClinVar):** DNAH5-related disorders, Primary ciliary dyskinesia 3, Primary ciliary dyskinesia, not provided, none provided, Ciliary dyskinesia.

## Similar variants {#similar}

Related DNAH5 variant pages (same residue, condition, or type): [DNAH5 p.Pro3606=](/variant/dnah5-p-pro3606), [DNAH5 c.2577+2del](/variant/dnah5-c-2577-plus-2del), [DNAH5 c.54_57+5del](/variant/dnah5-c-54-57-plus-5del), [DNAH5 c.7609+1_7609+3del](/variant/dnah5-c-7609-plus-1-7609-plus-3del), [DNAH5 c.9605+1del](/variant/dnah5-c-9605-plus-1del), [DNAH5 p.Ala1977fs](/variant/dnah5-p-ala1977fs), [DNAH5 p.Ala278fs](/variant/dnah5-p-ala278fs), [DNAH5 p.Ala3121_Leu3122insTer](/variant/dnah5-p-ala3121-leu3122inster).

### 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 65636). 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.*