# NM_001369.3(DNAH5):c.2674del (p.Val892fs)

https://sugi.bio/variant/dnah5-p-val892fs

## Summary

**DNAH5 p.Val892fs (c.2674del)** is classified **Pathogenic/Likely pathogenic** in DNAH5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-02). Very rare (popmax 0.00268%, afr); Associated with primary ciliary dyskinesia.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1772380356 · 2 submitters · 1 linked condition · very rare (popmax 0.00268%, afr)

## For patients & families {#patients}

This is a change in the DNAH5 gene that is considered likely disease-causing, submitted by 2 submitters, 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 | DNAH5 is a diagnostic-grade gene on 7 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 | [DNAH5](https://sugi.bio/atlas/gene/DNAH5/) |
| Protein change (HGVS p.) | p.Val892fs |
| Coding change (HGVS c.) | c.2674del |
| MANE Select transcript | [NM_001369](https://www.ncbi.nlm.nih.gov/nuccore/NM_001369) |
| dbSNP | [rs1772380356](https://www.ncbi.nlm.nih.gov/snp/rs1772380356/) |
| Variant type | Deletion |
| Location | chr5:13886033-13886033 (GRCh38) |
| ClinVar | [VCV1993031](https://www.ncbi.nlm.nih.gov/clinvar/variation/1993031/) |

**All HGVS expressions:** `NC_000005.10:g.13886033del`, `NC_000005.9:g.13886142del`, `NG_013081.2:g.63448del`, `NM_001369.2:c.2674delG`, `NM_001369.3:c.2674del`

## 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 3.36, GERP -0.799, phastCons 0.077 — 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 18 of 79**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 22.3**. 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 **0.00268%** (afr) · FAF95 0.000444% · FAF99 0.000166% · 2/74,744 in the highest group · 2/1,612,906 alleles overall — very rare (popmax 0.00268%, afr).

*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 **892** lies in the 'stem' region.

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

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-05-02.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-28 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-02 |

## 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 DNAH5 variant pages (same residue, condition, or type): [DNAH5 c.2577+2del](/variant/dnah5-c-2577-plus-2del), [DNAH5 c.54_57+5del](/variant/dnah5-c-54-57-plus-5del), [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), [DNAH5 p.Ala318fs](/variant/dnah5-p-ala318fs), [DNAH5 p.Ala3213fs](/variant/dnah5-p-ala3213fs).

### 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 1993031). 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.*