# NM_203447.4(DOCK8):c.1797G>A (p.Pro599=)

https://sugi.bio/variant/dock8-p-pro599

## Summary

**DOCK8 p.Pro599= (c.1797G>A)** is classified **Uncertain significance** in DOCK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-01). Very rare (popmax 0.0011%, sas); Associated with combined immunodeficiency due to DOCK8 deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1348614394 · 1 submitter · 1 linked condition · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the DOCK8 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Pro599= |
| Coding change (HGVS c.) | c.1797G>A |
| MANE Select transcript | [NM_203447](https://www.ncbi.nlm.nih.gov/nuccore/NM_203447) |
| dbSNP | [rs1348614394](https://www.ncbi.nlm.nih.gov/snp/rs1348614394/) |
| Variant type | single nucleotide variant |
| Location | chr9:368135-368135 (GRCh38) |
| ClinVar | [VCV946041](https://www.ncbi.nlm.nih.gov/clinvar/variation/946041/) |

**All HGVS expressions:** `LRG_196:g.158271G>A`, `LRG_196t1:c.1797G>A`, `NC_000009.11:g.368135G>A`, `NC_000009.12:g.368135G>A`, `NG_017007.1:g.158271G>A`, `NM_001190458.2:c.1593G>A`, `NM_001193536.2:c.1593G>A`, `NM_203447.4:c.1797G>A`

## Computational & population evidence {#evidence}

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

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.606, GERP -5.19, phastCons 0.996 — weakly conserved position
- CADD: **PHRED 21.6**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.14**, acceptor gain **0.00**, donor gain **0.23**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.14**, acceptor gain **0.00**, donor gain **0.23**.
- Pangolin: Δ**0.20** (loss), gain 0.01 / loss 0.20. SpliceAI calls gain. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 0.000183% · FAF99 0.00012% · 1/91,050 in the highest group · 7/1,612,628 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,050 |
| European (non-Finnish) | 0.000509% | 196,441 |

*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 **599** lies in the c2 dock-type 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.Pro599= falls in the c2 dock-type 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-11-01.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-11-01 |

## 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, HIES autosomal recessive, HYPER-IgE RECURRENT INFECTION SYNDROME 2, AUTOSOMAL RECESSIVE, HYPER-IgE SYNDROME 2, AUTOSOMAL RECESSIVE, WITH RECURRENT INFECTIONS, Hyper-IgE recurrent infection syndrome, autosomal recessive, DOCK8 Deficiency.

## Similar variants {#similar}

Related DOCK8 variant pages (same residue, condition, or type): [DOCK8 p.Pro599Leu](/variant/dock8-p-pro599leu), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 946041). 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.*