# NM_001369.3(DNAH5):c.13462C>A (p.Pro4488Thr)

https://sugi.bio/variant/dnah5-p-pro4488thr

## Summary

**DNAH5 p.Pro4488Thr (c.13462C>A)** is classified **Benign** in DNAH5 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). AlphaMissense: ambiguous (0.5141); Common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with primary ciliary dyskinesia.

**At a glance:** Benign · review: Multiple submitters · rsID rs113425437 · 10 submitters · 2 linked conditions · AlphaMissense ambiguous · common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the DNAH5 gene that is classified as benign — not considered disease-causing, submitted by 10 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.Pro4488Thr |
| Coding change (HGVS c.) | c.13462C>A |
| MANE Select transcript | [NM_001369](https://www.ncbi.nlm.nih.gov/nuccore/NM_001369) |
| dbSNP | [rs113425437](https://www.ncbi.nlm.nih.gov/snp/rs113425437/) |
| Variant type | single nucleotide variant |
| Location | chr5:13701313-13701313 (GRCh38) |
| ClinVar | [VCV226595](https://www.ncbi.nlm.nih.gov/clinvar/variation/226595/) |

**All HGVS expressions:** `NC_000005.10:g.13701313G>T`, `NC_000005.9:g.13701422G>T`, `NG_013081.2:g.248168C>A`, `NM_001369.3:c.13462C>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **ambiguous** (0.5141) — no call either way
- REVEL 0.324 (indeterminate)
- Conservation: phyloP 8.319, GERP 1.95, phastCons 1 — highly conserved
- CADD: **PHRED 22.9**. 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 0.90** across the covering region of the MANE Select transcript (13,691,987–13,716,559), spanning 24,572 bp. Chi-square p 0.038. 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 **12.8%** (afr) · FAF95 12.6% · FAF99 12.5% · 9,576/74,902 in the highest group · 11,032/1,613,832 alleles overall — common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 12.8% | 8 |
| Admixed American | 0.96% | 104 |
| Remaining individuals (not grpmax-eligible) | 0.917% | 109 |
| Middle Eastern | 0.693% | 144 |
| South Asian | 0.0472% | 2,118 |
| European (non-Finnish) | 0.0187% | 5,339 |
| East Asian | 0.00223% | 44,852 |

*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}


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

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (10/10 Benign).

**Submission history:** 10 submissions (2013–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2013-02-21 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2014-12-15 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2023-11-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2020-09-16 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-12-31 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Counsyl | Benign | no assertion criteria provided | clinical testing | 2017-03-06 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Primary ciliary dyskinesia, not specified, Primary ciliary dyskinesia 3, not provided, AllHighlyPenetrant, none provided, Ciliary dyskinesia.

## Similar variants {#similar}

Related DNAH5 variant pages (same residue, condition, or type): [DNAH5 p.Pro4488Leu](/variant/dnah5-p-pro4488leu), [DNAH5 p.Pro4488=](/variant/dnah5-p-pro4488), [DNAH5 p.Pro4488Ser](/variant/dnah5-p-pro4488ser), [DNAH5 c.10555+1G>C](/variant/dnah5-c-10555-plus-1g-c), [DNAH5 c.1089+1G>A](/variant/dnah5-c-1089-plus-1g-a), [DNAH5 c.11028+2T>C](/variant/dnah5-c-11028-plus-2t-c), [DNAH5 c.11029-2A>T](/variant/dnah5-c-11029-minus-2a-t), [DNAH5 c.11571-1G>A](/variant/dnah5-c-11571-minus-1g-a).

### 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 226595). 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.*