Is DOCK4 p.Pro1800Ser (c.5398C>T) pathogenic?

DOCK4 p.Pro1800Ser (c.5398C>T) is classified Uncertain significance in DOCK4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-16). AlphaMissense: ambiguous (0.5316); Very rare (popmax 8.54e-05%, nfe); Associated with DOCK4-related disorder.

What condition is associated with DOCK4 p.Pro1800Ser (c.5398C>T)?

DOCK4 p.Pro1800Ser (c.5398C>T) is associated with DOCK4-related disorder (ClinVar).

How common is DOCK4 p.Pro1800Ser (c.5398C>T) in the general population?

DOCK4 p.Pro1800Ser (c.5398C>T) is very rare (popmax 8.54e-05%, nfe) (gnomAD).

What do computational predictors say about DOCK4 p.Pro1800Ser (c.5398C>T)?

AlphaMissense predicts ambiguous (score 0.5316) — an in-silico prediction, not a clinical call.

DOCK4 p.Pro1800Ser

c.5398C>T · VCV3347204

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5316 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.54e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

DOCK4-related disorder

Computational evidence

Protein change
AlphaMissense	0.5316	ambiguous
REVEL	0.269	benign-leaning
SaProt	LLR -6.50	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.7, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 13 kb · p 0.00031 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1791S vs ClinVar P1800S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.54e-05% European (non-Finnish) · 1/1,170,792 alleles

Overall 6.93e-05% 1/1,443,788 alleles · very rare

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: DOCK4
Protein: p.Pro1800Ser
Coding: c.5398C>T
MANE Select: NM_001363540
Type: single nucleotide variant
Location: chr7:111735075 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.47
Residue 1800: the 'disordered' region

Full DOCK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DOCK4-related disorder

Similar variants

DOCK4 c.1192+9C>G Uncertain significance ★ same condition
DOCK4 p.Arg1429Gln Uncertain significance ★ ⚠ same condition
DOCK4 p.Arg283Ter Uncertain significance ★ same condition
DOCK4 p.Pro1835Leu Uncertain significance ★ ⚠ same condition
DOCK4 c.3316-10T>G Uncertain significance same condition
DOCK4 c.4417-2A>G Uncertain significance same condition
DOCK4 p.Gln1498Ter Uncertain significance same condition
DOCK4 p.Gly1038Ser 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/dock4-p-pro1800ser (accessed [today's date]).

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