Is DOCK4 p.Ser1817Tyr (c.5450C>A) pathogenic?

DOCK4 p.Ser1817Tyr (c.5450C>A) is classified Uncertain significance in DOCK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). AlphaMissense: likely benign (0.1647); Very rare (popmax 0.000763%, nfe).

How common is DOCK4 p.Ser1817Tyr (c.5450C>A) in the general population?

DOCK4 p.Ser1817Tyr (c.5450C>A) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about DOCK4 p.Ser1817Tyr (c.5450C>A)?

AlphaMissense predicts likely benign (score 0.1647) — an in-silico prediction, not a clinical call.

DOCK4 p.Ser1817Tyr

c.5450C>A · rs766423135 · VCV2612415

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1647	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -10.60	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 13 kb · p 0.00031 · regional, not allelic
Overall
CADD	24.4	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 S1808Y vs ClinVar S1817Y) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,906 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,908 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.Ser1817Tyr
Coding: c.5450C>A
MANE Select: NM_001363540
dbSNP: rs766423135
Type: single nucleotide variant
Location: chr7:111732257 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.47
Residue 1817: the 'disordered' region

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

Similar variants

DOCK4 p.Arg490Trp Uncertain significance ★★ ⚠ same type
DOCK4 p.Gln1223Arg Uncertain significance ★★ ⚠ same type
DOCK4 p.His1716Tyr Uncertain significance ★★ ⚠ same type
DOCK4 p.Pro1641Leu Uncertain significance ★★ ⚠ same type
DOCK4 p.Ser750Arg Uncertain significance ★★ ⚠ same type
DOCK4 c.550-8T>C Benign/Likely benign ★★ same type
DOCK4 p.Arg106Cys Benign/Likely benign ★★ ⚠ same type
DOCK4 p.Arg106His Benign/Likely benign ★★ 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/dock4-p-ser1817tyr (accessed [today's date]).

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