Is DOCK8 p.Glu99Lys (c.295G>A) pathogenic?

DOCK8 p.Glu99Lys (c.295G>A) is classified Uncertain significance in DOCK8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-27). AlphaMissense: likely benign (0.2264); Rare (popmax 0.138%, sas).

How common is DOCK8 p.Glu99Lys (c.295G>A) in the general population?

DOCK8 p.Glu99Lys (c.295G>A) is rare (popmax 0.138%, sas) (gnomAD).

What do computational predictors say about DOCK8 p.Glu99Lys (c.295G>A)?

AlphaMissense predicts likely benign (score 0.2264) — an in-silico prediction, not a clinical call.

DOCK8 p.Glu99Lys

c.295G>A · rs547012088 · VCV652068

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2264 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.138%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2264	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -2.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.47	donor gain · deltas
Pangolin	Δ0.22	gain · loss 0.07 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	32.0	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 0.138% South Asian · 126/91,074 alleles

Filtering AF 0.119% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.111%

Overall 0.00843% 136/1,613,958 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.138%	723
Middle Eastern	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.0112%	8,927
European (non-Finnish)	0.00017%	589,957

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.Glu99Lys
Coding: c.295G>A
MANE Select: NM_203447
dbSNP: rs547012088
Type: single nucleotide variant
Location: chr9:286599 (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.Glu99Gly 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
DOCK8 p.Arg1388Ter 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-glu99lys (accessed [today's date]).

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