Is DOCK2 p.Arg1696Trp (c.5086C>T) pathogenic?

DOCK2 p.Arg1696Trp (c.5086C>T) is classified Uncertain significance in DOCK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-08). AlphaMissense: ambiguous (0.562); Very rare (popmax 0.00333%, amr); Associated with DOCK2 deficiency.

What condition is associated with DOCK2 p.Arg1696Trp (c.5086C>T)?

DOCK2 p.Arg1696Trp (c.5086C>T) is associated with DOCK2 deficiency (ClinVar).

How common is DOCK2 p.Arg1696Trp (c.5086C>T) in the general population?

DOCK2 p.Arg1696Trp (c.5086C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about DOCK2 p.Arg1696Trp (c.5086C>T)?

AlphaMissense predicts ambiguous (score 0.562) — an in-silico prediction, not a clinical call.

DOCK2 p.Arg1696Trp

Q: How is Combined immunodeficiency due to DOCK2 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.5086C>T · rs980056604 · VCV653097

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.562 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

DOCK2 deficiency

Computational evidence

Protein change
AlphaMissense	0.562	ambiguous
REVEL	0.115	moderately benign-leaning
SaProt	LLR -9.89	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 2.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 33 kb · p 0.0025 · regional, not allelic
Overall
CADD	28.4	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 0.00333% Admixed American · 2/60,012 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00161% 26/1,613,994 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,006
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.00161%	62,107
Finnishnot grpmax-eligible	0.00156%	64,026
African / African-American	0.00134%	74,878
South Asian	0.0011%	91,084

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: DOCK2
Protein: p.Arg1696Trp
Coding: c.5086C>T
MANE Select: NM_004946
dbSNP: rs980056604
Type: single nucleotide variant
Location: chr5:170079066 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.40 · 6 PDB
Residue 1696: the 'disordered' region

Full DOCK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DOCK2 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to DOCK2 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DOCK2 p.Arg1696Gln Uncertain significance ★★ ⚠ same residue
DOCK2 c.2267+3G>A Uncertain significance ★★ same condition
DOCK2 c.2704-3C>T Uncertain significance ★★ same condition
DOCK2 c.4467+4A>G Uncertain significance ★★ same condition
DOCK2 p.Ala1393Val Uncertain significance ★★ ⚠ same condition
DOCK2 p.Ala1710Val Uncertain significance ★★ ⚠ same condition
DOCK2 p.Ala1765Val Uncertain significance ★★ ⚠ same condition
DOCK2 p.Ala24Pro Uncertain significance ★★ ⚠ 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/dock2-p-arg1696trp (accessed [today's date]).

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