# NM_203447.4(DOCK8):c.5832G>A (p.Pro1944=)

https://sugi.bio/variant/dock8-p-pro1944

## Summary

**DOCK8 p.Pro1944= (c.5832G>A)** is classified **Benign/Likely benign** in DOCK8 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 15%, afr) — too common for a highly-penetrant pathogenic allele; Associated with combined immunodeficiency due to DOCK8 deficiency.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs10491684 · 8 submitters · 1 linked condition · common (popmax 15%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the DOCK8 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 8 submitters, and is linked to combined immunodeficiency due to DOCK8 deficiency.

*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 recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DOCK8 is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Combined immunodeficiency due to DOCK8 deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Chronic otitis media — Very frequent (99-80%)
- Atopic dermatitis — Very frequent (99-80%)
- Pneumonia — Very frequent (99-80%)
- Asthma — Very frequent (99-80%)
- Recurrent respiratory infections — Very frequent (99-80%)
- Increased circulating IgE level — Very frequent (99-80%)
- Recurrent viral infections — Very frequent (99-80%)
- Recurrent candida infections — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002816/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DOCK8](https://sugi.bio/atlas/gene/DOCK8/) |
| Protein change (HGVS p.) | p.Pro1944= |
| Coding change (HGVS c.) | c.5832G>A |
| MANE Select transcript | [NM_203447](https://www.ncbi.nlm.nih.gov/nuccore/NM_203447) |
| dbSNP | [rs10491684](https://www.ncbi.nlm.nih.gov/snp/rs10491684/) |
| Variant type | single nucleotide variant |
| Location | chr9:449798-449798 (GRCh38) |
| ClinVar | [VCV137153](https://www.ncbi.nlm.nih.gov/clinvar/variation/137153/) |

**All HGVS expressions:** `LRG_196:g.239934G>A`, `LRG_196t1:c.5832G>A`, `NC_000009.11:g.449798G>A`, `NC_000009.12:g.449798G>A`, `NG_017007.1:g.239934G>A`, `NM_001190458.2:c.5532G>A`, `NM_001193536.2:c.5628G>A`, `NM_203447.4:c.5832G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 15%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 -2.966, GERP -5.25 — fast-evolving / accelerated position
- CADD: **PHRED 6.274**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.38 acceptor gain), 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 **15%** (afr) · FAF95 14.7% · FAF99 14.6% · 11,205/74,906 in the highest group · 115,751/1,612,724 alleles overall — common (popmax 15%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 15% | 7 |
| Ashkenazi Jewish (not grpmax-eligible) | 9.32% | 11 |
| Middle Eastern | 8.66% | 12 |
| Finnish (not grpmax-eligible) | 8.52% | 12 |
| Remaining individuals (not grpmax-eligible) | 7.19% | 14 |
| European (non-Finnish) | 7.17% | 14 |
| Admixed American | 5.01% | 20 |
| South Asian | 4.15% | 24 |
| Amish (not grpmax-eligible) | 2.53% | 40 |
| East Asian | 0.0267% | 3,739 |

*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}

**DOCK8** population constraint: LOEUF 0.622, pLI 2.9093e-17, missense-Z -1.7115. *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):

- **combined immunodeficiency due to DOCK8 deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **1944** lies in the docker domain.

AlphaFold model confidence (whole protein): pLDDT 75.17, 27% of residues very-high.

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

*Describes the biological roles of DOCK8 (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:** DOCK8's established molecular role includes guanyl-nucleotide exchange factor activity. p.Pro1944= falls in the docker domain.


### Pathways affected {#pathways}

DOCK8 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RHOJ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013409) | curated |

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

**Molecular function:** guanyl-nucleotide exchange factor activity.

**Biological process:** positive regulation of GTPase activity, memory T cell proliferation, positive regulation of establishment of T cell polarity, cellular response to chemokine, positive regulation of T cell migration.

## Clinical significance {#significance}

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

**Submitter consensus:** conflicting (7 Benign, 1 Likely benign).

**Submission history:** 8 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2014-03-11 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2013-02-21 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2019-03-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-21 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

## Associated conditions {#conditions}

[combined immunodeficiency due to DOCK8 deficiency](https://sugi.bio/atlas/disease/combined-immunodeficiency-due-to-dock8-deficiency/).

**Reported phenotype names (ClinVar):** Combined immunodeficiency due to DOCK8 deficiency, not specified, not provided, none provided, AllHighlyPenetrant, Hyper-IgE recurrent infection syndrome, autosomal recessive, HYPER-IgE RECURRENT INFECTION SYNDROME 2, AUTOSOMAL RECESSIVE, DOCK8 Deficiency, HIES autosomal recessive, HYPER-IgE SYNDROME 2, AUTOSOMAL RECESSIVE, WITH RECURRENT INFECTIONS.

## Pharmacogenomics (PharmGKB) {#pgx}

Clinical drug-response annotations:

| Drug(s) | Evidence level | Category | Phenotype |
| --- | --- | --- | --- |
| carboplatin;gemcitabine | 3 | Toxicity | Non-Small Cell Lung Carcinoma;Thrombocytopenia |
*PharmGKB levels 1A/1B (highest) → 4. Discuss any medication decision with your prescriber — reference information, not advice.*

## Similar variants {#similar}

Related DOCK8 variant pages (same residue, condition, or type): [DOCK8 c.1680-2A>G](/variant/dock8-c-1680-minus-2a-g), [DOCK8 c.2779-2A>C](/variant/dock8-c-2779-minus-2a-c), [DOCK8 c.2971-1G>A](/variant/dock8-c-2971-minus-1g-a), [DOCK8 c.3530+1G>A](/variant/dock8-c-3530-plus-1g-a), [DOCK8 c.528+1G>A](/variant/dock8-c-528-plus-1g-a), [DOCK8 c.529-2A>G](/variant/dock8-c-529-minus-2a-g), [DOCK8 p.Arg1388Ter](/variant/dock8-p-arg1388ter), [DOCK8 p.Arg1796Ter](/variant/dock8-p-arg1796ter).

### 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 137153). 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.*