Is DOCK2 p.Ser593Phe (c.1778C>T) pathogenic?

DOCK2 p.Ser593Phe (c.1778C>T) is classified Uncertain significance in DOCK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-28). AlphaMissense: likely benign (0.2429); Ultra-rare (popmax 0.0165%, mid); Associated with DOCK2 deficiency.

What condition is associated with DOCK2 p.Ser593Phe (c.1778C>T)?

DOCK2 p.Ser593Phe (c.1778C>T) is associated with DOCK2 deficiency (ClinVar).

How common is DOCK2 p.Ser593Phe (c.1778C>T) in the general population?

DOCK2 p.Ser593Phe (c.1778C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about DOCK2 p.Ser593Phe (c.1778C>T)?

AlphaMissense predicts likely benign (score 0.2429) — an in-silico prediction, not a clinical call.

DOCK2 p.Ser593Phe

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.1778C>T · rs2113536062 · VCV1375993

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2429 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

DOCK2 deficiency

Computational evidence

Protein change
AlphaMissense	0.2429	likely benign
REVEL	0.34	indeterminate
SaProt	LLR -9.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 348 kb · p 3.1e-21 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Overall 6.2e-05% 1/1,613,844 alleles · ultra-rare exomes 1/1,461,530 · genomes 0/152,314 · joint denominator

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.Ser593Phe
Coding: c.1778C>T
MANE Select: NM_004946
dbSNP: rs2113536062
Type: single nucleotide variant
Location: chr5:169714146 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.40 · 6 PDB
Residue 593: the c2 dock-type domain; a modified residue (phosphoserine)

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 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
DOCK2 p.Ala454Val 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-ser593phe (accessed [today's date]).

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