Is DOCK8 p.Arg899Trp (c.2695C>T) pathogenic?

DOCK8 p.Arg899Trp (c.2695C>T) is classified Uncertain significance in DOCK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: ambiguous (0.4356); Ultra-rare (popmax 0.0283%, amr).

How common is DOCK8 p.Arg899Trp (c.2695C>T) in the general population?

DOCK8 p.Arg899Trp (c.2695C>T) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about DOCK8 p.Arg899Trp (c.2695C>T)?

AlphaMissense predicts ambiguous (score 0.4356) — an in-silico prediction, not a clinical call.

DOCK8 p.Arg899Trp

c.2695C>T · rs371022243 · VCV1007570

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4356 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4356	ambiguous
REVEL	0.283	benign-leaning
SaProt	LLR -10.83	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	27.2	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 0.0283% Admixed American · 17/59,986 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00297% 48/1,613,940 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0283%	3,529
South Asian	0.0132%	7,590
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.00144%	69,411

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.Arg899Trp
Coding: c.2695C>T
MANE Select: NM_203447
dbSNP: rs371022243
Type: single nucleotide variant
Location: chr9:382602 (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 p.Arg899Gln Uncertain significance ★ ⚠ same residue
DOCK8 p.Arg899Pro Uncertain significance ★ same residue
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

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-arg899trp (accessed [today's date]).

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