Is DOCK4 p.Val420Met (c.1258G>A) pathogenic?

DOCK4 p.Val420Met (c.1258G>A) is classified Uncertain significance in DOCK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-12). AlphaMissense: likely pathogenic (0.9069); Very rare (popmax 0.00834%, amr); Associated with neurodevelopmental disorder.

What condition is associated with DOCK4 p.Val420Met (c.1258G>A)?

DOCK4 p.Val420Met (c.1258G>A) is associated with neurodevelopmental disorder (ClinVar).

How common is DOCK4 p.Val420Met (c.1258G>A) in the general population?

DOCK4 p.Val420Met (c.1258G>A) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about DOCK4 p.Val420Met (c.1258G>A)?

AlphaMissense predicts likely pathogenic (score 0.9069) — an in-silico prediction, not a clinical call.

DOCK4 p.Val420Met

c.1258G>A · rs768165193 · VCV2627585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9069 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.9069	likely pathogenic
REVEL	0.277	benign-leaning
SaProt	LLR -2.65	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 465 kb · p 2.8e-18 · regional, not allelic
Overall
CADD	28.6	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 0.00834% Admixed American · 5/59,986 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00186% 30/1,612,392 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,997
Remaining individualsnot grpmax-eligible	0.0032%	31,210
African / African-American	0.00267%	37,434
European (non-Finnish)	0.00178%	56,131

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.Val420Met
Coding: c.1258G>A
MANE Select: NM_001363540
dbSNP: rs768165193
Type: single nucleotide variant
Location: chr7:111901736 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.47
Residue 420: the c2 dock-type domain

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

Disease context

neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DOCK4 p.Ile1067Thr Likely pathogenic ★ same condition
DOCK4 p.Met1044Thr Likely pathogenic ★ same condition
DOCK4 p.Thr982Ile Likely pathogenic ★ ⚠ same condition
DOCK4 p.Arg1347Gln Uncertain significance ★ ⚠ same condition
DOCK4 p.Arg298Ter Uncertain significance ★ same condition
DOCK4 p.Arg924Ter Uncertain significance ★ same condition
DOCK4 p.Lys1971Asn Uncertain significance ★ ⚠ same condition
DOCK4 p.Pro253Leu 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-val420met (accessed [today's date]).

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