Is DOCK8 p.Met1663Val (c.4987A>G) pathogenic?

DOCK8 p.Met1663Val (c.4987A>G) is classified Uncertain significance in DOCK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.1935); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DOCK8 p.Met1663Val (c.4987A>G)?

DOCK8 p.Met1663Val (c.4987A>G) is associated with Inborn genetic diseases (ClinVar).

How common is DOCK8 p.Met1663Val (c.4987A>G) in the general population?

DOCK8 p.Met1663Val (c.4987A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about DOCK8 p.Met1663Val (c.4987A>G)?

AlphaMissense predicts likely benign (score 0.1935) — an in-silico prediction, not a clinical call.

DOCK8 p.Met1663Val

c.4987A>G · VCV4617868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1935	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -7.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 0.33, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	22.4	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 8.47e-05% European (non-Finnish) · 1/1,180,056 alleles

Overall 0.00031% 5/1,613,938 alleles · very rare exomes 4/1,461,740 · genomes 1/152,198 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00469%	21,335
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)grpmax	8.47e-05%	1,180,057

Finnish 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.Met1663Val
Coding: c.4987A>G
MANE Select: NM_203447
Type: single nucleotide variant
Location: chr9:434883 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.17
Residue 1663: the docker domain

Full DOCK8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DOCK8 p.Ala1170Thr Uncertain significance ★★ ⚠ same condition
DOCK8 p.Ala1252Pro Uncertain significance ★★ ⚠ same condition
DOCK8 p.Ala1290Val Uncertain significance ★★ ⚠ same condition
DOCK8 p.Ala1383Gly Uncertain significance ★★ ⚠ same condition
DOCK8 p.Ala1579Gly Uncertain significance ★★ ⚠ same condition
DOCK8 p.Ala1736Val Uncertain significance ★★ ⚠ same condition
DOCK8 p.Ala2037Val Uncertain significance ★★ ⚠ same condition
DOCK8 p.Ala219Val 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-met1663val (accessed [today's date]).

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