Is DOCK8 p.Arg393His (c.1178G>A) pathogenic?

DOCK8 p.Arg393His (c.1178G>A) is classified Uncertain significance in DOCK8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-04). AlphaMissense: ambiguous (0.3416); Ultra-rare (popmax 0.0329%, mid).

How common is DOCK8 p.Arg393His (c.1178G>A) in the general population?

DOCK8 p.Arg393His (c.1178G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about DOCK8 p.Arg393His (c.1178G>A)?

AlphaMissense predicts ambiguous (score 0.3416) — an in-silico prediction, not a clinical call.

DOCK8 p.Arg393His

c.1178G>A · rs374952856 · VCV949403

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3416 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Computational evidence

Protein change
AlphaMissense	0.3416	ambiguous
REVEL	0.374	indeterminate
SaProt	LLR -7.05	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 2.8, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	29.5	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.00551% 89/1,614,086 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
European (non-Finnish)	0.00636%	15,734
Admixed American	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0048%	20,829
East Asian	0.00446%	22,445
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Finnishnot grpmax-eligible	0.00156%	64,032
African / African-American	0.00133%	74,948
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: DOCK8
Protein: p.Arg393His
Coding: c.1178G>A
MANE Select: NM_203447
dbSNP: rs374952856
Type: single nucleotide variant
Location: chr9:334277 (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

Similar variants

DOCK8 c.1680-2A>G Likely pathogenic ★★ same type
DOCK8 c.2779-2A>C Likely pathogenic ★★ same type
DOCK8 c.2971-1G>A Pathogenic ★★ same type
DOCK8 c.3530+1G>A Likely pathogenic ★★ same type
DOCK8 c.528+1G>A Likely pathogenic ★★ same type
DOCK8 c.529-2A>G Likely pathogenic ★★ same type
DOCK8 p.Arg1388Ter Pathogenic ★★ same type
DOCK8 p.Arg1796Ter Pathogenic ★★ same type

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-arg393his (accessed [today's date]).

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