Is DOCK4 p.Val1591Met (c.4771G>A) pathogenic?

DOCK4 p.Val1591Met (c.4771G>A) is classified Uncertain significance in DOCK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: likely benign (0.119); Very rare (popmax 0.0096%, nfe).

How common is DOCK4 p.Val1591Met (c.4771G>A) in the general population?

DOCK4 p.Val1591Met (c.4771G>A) is very rare (popmax 0.0096%, nfe) (gnomAD).

What do computational predictors say about DOCK4 p.Val1591Met (c.4771G>A)?

AlphaMissense predicts likely benign (score 0.119) — an in-silico prediction, not a clinical call.

DOCK4 p.Val1591Met

c.4771G>A · rs376404769 · VCV2205377

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.119 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0096%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.119	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -6.97	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 4.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 465 kb · p 2.8e-18 · regional, not allelic
Overall
CADD	23.2	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V1582M vs ClinVar V1591M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0096% European (non-Finnish) · 113/1,176,726 alleles

Filtering AF 0.00811% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00762%

Overall 0.00716% 115/1,606,390 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0096%	10,413
Remaining individualsnot grpmax-eligible	0.00322%	31,085

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.Val1591Met
Coding: c.4771G>A
MANE Select: NM_001363540
dbSNP: rs376404769
Type: single nucleotide variant
Location: chr7:111742039 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.47
Residue 1591: the docker domain

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

Similar variants

DOCK4 p.Val1591Leu Uncertain significance ★ ⚠ same residue
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

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-val1591met (accessed [today's date]).

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