# NM_023036.6(DNAI2):c.1631_1632insAGCG (p.Val545fs)

https://sugi.bio/variant/dnai2-p-val545fs

## Summary

**DNAI2 p.Val545fs (c.1631_1632insAGCG)** is classified **Likely pathogenic** in DNAI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-21). No gnomAD frequency available for this variant; Associated with primary ciliary dyskinesia 9.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2509774595 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DNAI2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to primary ciliary dyskinesia 9.

*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) |
| Diagnostic panels | DNAI2 is a diagnostic-grade gene on 4 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/0015558/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DNAI2](https://sugi.bio/atlas/gene/DNAI2/) |
| Protein change (HGVS p.) | p.Val545fs |
| Coding change (HGVS c.) | c.1631_1632insAGCG |
| MANE Select transcript | [NM_023036](https://www.ncbi.nlm.nih.gov/nuccore/NM_023036) |
| dbSNP | [rs2509774595](https://www.ncbi.nlm.nih.gov/snp/rs2509774595/) |
| Variant type | Insertion |
| Location | chr17:74312139-74312140 (GRCh38) |
| ClinVar | [VCV2439890](https://www.ncbi.nlm.nih.gov/clinvar/variation/2439890/) |

**All HGVS expressions:** `NC_000017.10:g.72308278_72308279insAGCG`, `NC_000017.11:g.74312139_74312140insAGCG`, `NG_016865.1:g.42893_42894insAGCG`, `NM_001172810.3:c.1595_1596insAGCG`, `NM_001353167.2:c.1631_1632insAGCG`, `NM_023036.6:c.1631_1632insAGCG`

## 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 4.074, GERP 1.06, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.966, pLI 9.4569e-16. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 12 of 14**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**DNAI2** population constraint: LOEUF 0.966, pLI 9.4569e-16, missense-Z 1.9448; 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 9** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.27, 54% of residues very-high.

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

## What this gene does {#gene-function}

*Describes the biological roles of DNAI2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** DNAI2's established molecular role includes microtubule motor activity.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** microtubule motor activity.

**Biological process:** cilium movement, determination of left/right symmetry, outer dynein arm assembly, cilium assembly.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-21.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-03-21 |

## Associated conditions {#conditions}

[primary ciliary dyskinesia 9](https://sugi.bio/atlas/disease/primary-ciliary-dyskinesia-9/).

**Reported phenotype names (ClinVar):** Primary ciliary dyskinesia 9, CILIARY DYSKINESIA, PRIMARY, 9, WITH OR WITHOUT SITUS INVERSUS.

## Similar variants {#similar}

Related DNAI2 variant pages (same residue, condition, or type): [DNAI2 c.1348-1G>A](/variant/dnai2-c-1348-minus-1g-a), [DNAI2 c.1494+1G>A](/variant/dnai2-c-1494-plus-1g-a), [DNAI2 c.346-3T>G](/variant/dnai2-c-346-minus-3t-g), [DNAI2 c.610+1G>A](/variant/dnai2-c-610-plus-1g-a), [DNAI2 p.Arg247Gln](/variant/dnai2-p-arg247gln), [DNAI2 p.Arg247Ter](/variant/dnai2-p-arg247ter), [DNAI2 p.Arg263Ter](/variant/dnai2-p-arg263ter), [DNAI2 p.Arg295Ter](/variant/dnai2-p-arg295ter).

### 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 2439890). 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.*