Is DOCK8 p.Glu1597Val (c.4790A>T) pathogenic?

DOCK8 p.Glu1597Val (c.4790A>T) is classified Uncertain significance in DOCK8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-19). AlphaMissense: ambiguous (0.3766); Ultra-rare (popmax 0.0109%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DOCK8 p.Glu1597Val (c.4790A>T)?

DOCK8 p.Glu1597Val (c.4790A>T) is associated with Inborn genetic diseases, combined immunodeficiency due to DOCK8 deficiency (ClinVar).

How common is DOCK8 p.Glu1597Val (c.4790A>T) in the general population?

DOCK8 p.Glu1597Val (c.4790A>T) is ultra-rare (popmax 0.0109%, nfe) (gnomAD).

What do computational predictors say about DOCK8 p.Glu1597Val (c.4790A>T)?

AlphaMissense predicts ambiguous (score 0.3766) — an in-silico prediction, not a clinical call.

DOCK8 p.Glu1597Val

c.4790A>T · rs373454848 · VCV570276

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3766 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3766	ambiguous
REVEL	0.231	benign-leaning
SaProt	LLR -5.54	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0109% European (non-Finnish) · 128/1,179,498 alleles

Filtering AF 0.00928% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00872%

Overall 0.00812% 131/1,613,478 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0109%	9,215
Remaining individualsnot grpmax-eligible	0.0048%	20,823

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DOCK8
Protein: p.Glu1597Val
Coding: c.4790A>T
MANE Select: NM_203447
dbSNP: rs373454848
Type: single nucleotide variant
Location: chr9:433879 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.17

Full DOCK8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined immunodeficiency due to DOCK8 deficiency

Similar variants

DOCK8 p.Glu1597= Likely benign ★★ same residue
DOCK8 c.1680-2A>G Likely pathogenic ★★ same condition
DOCK8 c.2779-2A>C Likely pathogenic ★★ same condition
DOCK8 c.2971-1G>A Pathogenic ★★ same condition
DOCK8 c.3530+1G>A Likely pathogenic ★★ same condition
DOCK8 c.528+1G>A Likely pathogenic ★★ same condition
DOCK8 c.529-2A>G Likely pathogenic ★★ same condition
DOCK8 p.Arg1388Ter Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dock8-p-glu1597val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown