# NM_001369.3(DNAH5):c.1427_1428del (p.Phe476fs)

https://sugi.bio/variant/dnah5-p-phe476fs

## Summary

**DNAH5 p.Phe476fs (c.1427_1428del)** is classified **Pathogenic** in DNAH5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-12-31). Very rare (popmax 0.000424%, nfe); Associated with DNAH5-related disorders.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs774493427 · 5 submitters · 3 linked conditions · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the DNAH5 gene that is considered disease-causing, submitted by 5 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.Phe476fs |
| Coding change (HGVS c.) | c.1427_1428del |
| MANE Select transcript | [NM_001369](https://www.ncbi.nlm.nih.gov/nuccore/NM_001369) |
| dbSNP | [rs774493427](https://www.ncbi.nlm.nih.gov/snp/rs774493427/) |
| Variant type | Deletion |
| Location | chr5:13913851-13913852 (GRCh38) |
| ClinVar | [VCV555559](https://www.ncbi.nlm.nih.gov/clinvar/variation/555559/) |

**All HGVS expressions:** `NC_000005.10:g.13913853_13913854del`, `NC_000005.9:g.13913962_13913963del`, `NG_013081.2:g.35629_35630del`, `NM_001369.2:c.1427_1428delTT`, `NM_001369.3:c.1427_1428del`

## 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 5.791, GERP 0.345, 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 11 of 79**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 33.0**. 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 **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,179,646 in the highest group · 5/1,613,530 alleles overall — very rare (popmax 0.000424%, nfe).

*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 **476** lies in the 'stem' 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 2024-12-31.

**Submitter consensus:** conflicting (4 Pathogenic, 1 Likely pathogenic).

**Submission history:** 5 submissions (2017–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2019-04-25 |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2017-12-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-09 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-31 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-11 |

## 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, 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.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), [DNAH5 p.Ala318fs](/variant/dnah5-p-ala318fs).

### 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 555559). 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.*