# NM_203447.4(DOCK8):c.3803del (p.Phe1268fs)

https://sugi.bio/variant/dock8-p-phe1268fs

## Summary

**DOCK8 p.Phe1268fs (c.3803del)** is classified **Pathogenic** in DOCK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-08). Very rare (popmax 0.000169%, nfe); Associated with combined immunodeficiency due to DOCK8 deficiency.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2056112807 · 1 submitter · 1 linked condition · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the DOCK8 gene that is reported as disease-causing, but on limited review, 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.Phe1268fs |
| Coding change (HGVS c.) | c.3803del |
| MANE Select transcript | [NM_203447](https://www.ncbi.nlm.nih.gov/nuccore/NM_203447) |
| dbSNP | [rs2056112807](https://www.ncbi.nlm.nih.gov/snp/rs2056112807/) |
| Variant type | Deletion |
| Location | chr9:418168-418168 (GRCh38) |
| ClinVar | [VCV839960](https://www.ncbi.nlm.nih.gov/clinvar/variation/839960/) |

**All HGVS expressions:** `LRG_196:g.208306del`, `LRG_196t1:c.3803del`, `NC_000009.11:g.418170del`, `NC_000009.12:g.418170del`, `NG_017007.1:g.208306del`, `NM_001190458.2:c.3503del`, `NM_001193536.2:c.3599del`, `NM_203447.4:c.3803del`

## 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 8.184, GERP 2.42, phastCons 0.964 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.622, pLI 2.9093e-17. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 30 of 48**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,180,040 in the highest group · 2/1,461,890 alleles overall — very rare (popmax 0.000169%, nfe).

*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}


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.


### 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-08.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-08 |

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

## Similar variants {#similar}

Related DOCK8 variant pages (same residue, condition, or type): [DOCK8 p.Leu1754fs](/variant/dock8-p-leu1754fs), [DOCK8 p.Phe1113fs](/variant/dock8-p-phe1113fs), [DOCK8 p.Tyr491fs](/variant/dock8-p-tyr491fs), [DOCK8 c.2109+11del](/variant/dock8-c-2109-plus-11del), [DOCK8 c.3234+15del](/variant/dock8-c-3234-plus-15del), [DOCK8 c.3234+8del](/variant/dock8-c-3234-plus-8del), [DOCK8 c.333-8del](/variant/dock8-c-333-minus-8del), [DOCK8 c.404+16del](/variant/dock8-c-404-plus-16del).

### 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 839960). 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.*