Is DOCK2 p.Pro1340Ser (c.4018C>T) pathogenic?

DOCK2 p.Pro1340Ser (c.4018C>T) is classified Uncertain significance in DOCK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-12). AlphaMissense: likely pathogenic (0.8077); Ultra-rare (popmax 0.0164%, mid); Associated with DOCK2 deficiency.

What condition is associated with DOCK2 p.Pro1340Ser (c.4018C>T)?

DOCK2 p.Pro1340Ser (c.4018C>T) is associated with DOCK2 deficiency (ClinVar).

How common is DOCK2 p.Pro1340Ser (c.4018C>T) in the general population?

DOCK2 p.Pro1340Ser (c.4018C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about DOCK2 p.Pro1340Ser (c.4018C>T)?

AlphaMissense predicts likely pathogenic (score 0.8077) — an in-silico prediction, not a clinical call.

DOCK2 p.Pro1340Ser

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.4018C>T · rs752947346 · VCV645999

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8077 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

DOCK2 deficiency

Computational evidence

Protein change
AlphaMissense	0.8077	likely pathogenic
REVEL	0.31	indeterminate
SaProt	LLR -14.07	damaging
⇒ AlphaMissense and SaProt both call this damaging; 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 2.8, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 348 kb · p 3.1e-21 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00112% 18/1,613,874 alleles · ultra-rare exomes 17/1,461,644 · genomes 1/152,230 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Remaining individualsnot grpmax-eligible	0.0032%	31,239
African / African-American	0.00133%	74,920
European (non-Finnish)	0.00119%	84,282

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.Pro1340Ser
Coding: c.4018C>T
MANE Select: NM_004946
dbSNP: rs752947346
Type: single nucleotide variant
Location: chr5:170047561 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.40 · 6 PDB
Residue 1340: the docker domain; the 'interaction with crkl' region; an α-helix

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-pro1340ser (accessed [today's date]).

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