Is DOCK8 p.Ala13Pro (c.37G>C) pathogenic?

DOCK8 p.Ala13Pro (c.37G>C) is classified Uncertain significance in DOCK8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-25). AlphaMissense: likely pathogenic (0.9351); Very rare (popmax 0.00102%, nfe); Associated with hyper-IgE recurrent infection syndrome 3, autosomal recessive.

What condition is associated with DOCK8 p.Ala13Pro (c.37G>C)?

DOCK8 p.Ala13Pro (c.37G>C) is associated with hyper-IgE recurrent infection syndrome 3, autosomal recessive (ClinVar).

How common is DOCK8 p.Ala13Pro (c.37G>C) in the general population?

DOCK8 p.Ala13Pro (c.37G>C) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about DOCK8 p.Ala13Pro (c.37G>C)?

AlphaMissense predicts likely pathogenic (score 0.9351) — an in-silico prediction, not a clinical call.

DOCK8 p.Ala13Pro

Q: How is Autosomal recessive hyper-IgE syndrome due to ZNF341 deficiency inherited?

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

c.37G>C · rs749272308 · VCV1061220

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9351 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyper-IgE recurrent infection syndrome 3, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9351	likely pathogenic · top 7% in DOCK8
REVEL	0.147	moderately benign-leaning
SaProt	LLR -5.65	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	25.7	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 0.00102% European (non-Finnish) · 12/1,174,590 alleles

Filtering AF 0.000545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00043%

Overall 0.000903% 13/1,439,898 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00162%	61,794
European (non-Finnish)grpmax	0.00102%	97,883

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala13Pro
Coding: c.37G>C
MANE Select: NM_203447
dbSNP: rs749272308
Type: single nucleotide variant
Location: chr9:215013 (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

hyper-IgE recurrent infection syndrome 3, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive hyper-IgE syndrome due to ZNF341 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

DOCK8 p.Ala13= Uncertain significance ★ same residue
DOCK8 p.Ala13Thr Uncertain significance ★ ⚠ same residue
DOCK8 p.Ala1761Val Uncertain significance ★★ ⚠ same condition
DOCK8 p.Ala229Asp Uncertain significance ★★ ⚠ same condition
DOCK8 p.Arg1015Cys Uncertain significance ★★ ⚠ same condition
DOCK8 p.Arg1238Cys Uncertain significance ★★ ⚠ same condition
DOCK8 p.Arg1294Cys Uncertain significance ★★ ⚠ same condition
DOCK8 p.Arg1904Gln 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/dock8-p-ala13pro (accessed [today's date]).

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