Is DOCK8 p.Pro364Ser (c.1090C>T) pathogenic?

DOCK8 p.Pro364Ser (c.1090C>T) is classified Uncertain significance in DOCK8 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-02-05). AlphaMissense: likely pathogenic (0.7369); Ultra-rare (popmax 0.0605%, nfe).

How common is DOCK8 p.Pro364Ser (c.1090C>T) in the general population?

DOCK8 p.Pro364Ser (c.1090C>T) is ultra-rare (popmax 0.0605%, nfe) (gnomAD).

What do computational predictors say about DOCK8 p.Pro364Ser (c.1090C>T)?

AlphaMissense predicts likely pathogenic (score 0.7369) — an in-silico prediction, not a clinical call.

DOCK8 p.Pro364Ser

c.1090C>T · rs146777948 · VCV452103

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7369 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0605%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7369	likely pathogenic
REVEL	0.476	indeterminate
SaProt	LLR -4.57	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.8, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	26.4	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 0.0605% European (non-Finnish) · 714/1,179,312 alleles

Filtering AF 0.0568% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0554%

Overall 0.047% 758/1,612,820 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0605%	1,652
Remaining individualsnot grpmax-eligible	0.0496%	2,015
African / African-American	0.0134%	7,469
Finnishnot grpmax-eligible	0.00469%	21,317

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.Pro364Ser
Coding: c.1090C>T
MANE Select: NM_203447
dbSNP: rs146777948
Type: single nucleotide variant
Location: chr9:332443 (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.Pro364Thr Uncertain significance ★★ ⚠ same residue
DOCK8 p.Pro364Arg Likely benign ⚠ 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-pro364ser (accessed [today's date]).

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