# NM_023036.6(DNAI2):c.571C>T (p.Pro191Ser)

https://sugi.bio/variant/dnai2-p-pro191ser

## Summary

**DNAI2 p.Pro191Ser (c.571C>T)** is classified **Conflicting classifications of pathogenicity** in DNAI2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-20). AlphaMissense: likely benign (0.1035); Ultra-rare (popmax 0.0164%, mid); Associated with primary ciliary dyskinesia 9.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs201457010 · 7 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0164%, mid)

## For patients & families {#patients}

This is a change in the DNAI2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, 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.Pro191Ser |
| Coding change (HGVS c.) | c.571C>T |
| MANE Select transcript | [NM_023036](https://www.ncbi.nlm.nih.gov/nuccore/NM_023036) |
| dbSNP | [rs201457010](https://www.ncbi.nlm.nih.gov/snp/rs201457010/) |
| Variant type | single nucleotide variant |
| Location | chr17:74289697-74289697 (GRCh38) |
| ClinVar | [VCV228613](https://www.ncbi.nlm.nih.gov/clinvar/variation/228613/) |

**All HGVS expressions:** `NC_000017.10:g.72285836C>T`, `NC_000017.11:g.74289697C>T`, `NG_016865.1:g.20451C>T`, `NM_001172810.3:c.571C>T`, `NM_001353167.2:c.571C>T`, `NM_023036.6:c.571C>T`, `NR_148379.2:n.572C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1035)
- REVEL 0.188 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.483 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.56, GERP 1.52, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 17.09**. 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 0.86** across the covering region of the MANE Select transcript (74,281,818–74,314,213), spanning 32,395 bp. Chi-square p 4.8e-05. 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 **0.0164%** (mid) · FAF95 0.0135% · FAF99 0.0128% · 1/6,084 in the highest group · 314/1,613,878 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.368% | 272 |
| Remaining individuals (not grpmax-eligible) | 0.0288% | 3,471 |
| Middle Eastern (grpmax) | 0.0164% | 6,084 |
| European (non-Finnish) | 0.0153% | 6,519 |
| African / African-American | 0.00267% | 37,428 |
| East Asian | 0.00223% | 44,868 |
| Admixed American | 0.00167% | 59,960 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,004 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-20.

**Submitter consensus:** conflicting (4 Likely benign, 3 Uncertain significance).

**Submission history:** 7 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-05-12 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-16 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2018-02-07 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-01-17 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-20 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Primary ciliary dyskinesia 9, not specified, Primary ciliary dyskinesia, AllHighlyPenetrant, CILIARY DYSKINESIA, PRIMARY, 9, WITH OR WITHOUT SITUS INVERSUS, Ciliary dyskinesia.

## 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.1494+1G>T](/variant/dnai2-c-1494-plus-1g-t), [DNAI2 c.1495-2A>T](/variant/dnai2-c-1495-minus-2a-t), [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 c.610+1G>T](/variant/dnai2-c-610-plus-1g-t), [DNAI2 c.725-2A>C](/variant/dnai2-c-725-minus-2a-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 228613). 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.*