# NM_001369.3(DNAH5):c.8837G>A (p.Arg2946His)

https://sugi.bio/variant/dnah5-p-arg2946his

## Summary

**DNAH5 p.Arg2946His (c.8837G>A)** is classified **Conflicting classifications of pathogenicity** in DNAH5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-19). AlphaMissense: likely benign (0.1425); Ultra-rare (popmax 0.06%, afr); Associated with primary ciliary dyskinesia.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs140975593 · 4 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.06%, afr)

## For patients & families {#patients}

This is a change in the DNAH5 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 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.Arg2946His |
| Coding change (HGVS c.) | c.8837G>A |
| MANE Select transcript | [NM_001369](https://www.ncbi.nlm.nih.gov/nuccore/NM_001369) |
| dbSNP | [rs140975593](https://www.ncbi.nlm.nih.gov/snp/rs140975593/) |
| Variant type | single nucleotide variant |
| Location | chr5:13780943-13780943 (GRCh38) |
| ClinVar | [VCV660910](https://www.ncbi.nlm.nih.gov/clinvar/variation/660910/) |

**All HGVS expressions:** `NC_000005.10:g.13780943C>T`, `NC_000005.9:g.13781052C>T`, `NG_013081.2:g.168538G>A`, `NM_001369.3:c.8837G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1425)
- REVEL 0.35 (indeterminate)
- Conservation: phyloP 3.32, GERP 1.88, phastCons 0.964 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.4**. 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 0.98** across the covering region of the MANE Select transcript (13,716,643–13,944,438), spanning 227,795 bp. Chi-square p 0.16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.26 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.06%** (afr) · FAF95 0.046% · FAF99 0.0411% · 45/74,982 in the highest group · 102/1,613,554 alleles overall — ultra-rare (popmax 0.06%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.06% | 1,666 |
| South Asian | 0.0384% | 2,602 |
| Remaining individuals (not grpmax-eligible) | 0.0224% | 4,461 |
| Middle Eastern | 0.0165% | 6,052 |
| East Asian | 0.00446% | 22,424 |
| Admixed American | 0.00167% | 59,976 |
| European (non-Finnish) | 0.000339% | 294,925 |

*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 **2946** lies in the 'aaa 4' region.

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

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-07-19.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Benign).

**Submission history:** 4 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2019-12-31 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-09 |
| Breakthrough Genomics, Breakthrough Genomics | Uncertain significance | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-07-19 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related DNAH5 variant pages (same residue, condition, or type): [DNAH5 p.Arg2946Cys](/variant/dnah5-p-arg2946cys), [DNAH5 p.Arg2946Leu](/variant/dnah5-p-arg2946leu), [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), [DNAH5 c.12910-1G>C](/variant/dnah5-c-12910-minus-1g-c).

### 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 660910). 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.*