Is DOCK1 p.Met760Ile (c.2280G>A) pathogenic?

DOCK1 p.Met760Ile (c.2280G>A) is classified Uncertain significance in DOCK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-16). AlphaMissense: likely pathogenic (0.6169); Very rare (popmax 0.00017%, nfe).

How common is DOCK1 p.Met760Ile (c.2280G>A) in the general population?

DOCK1 p.Met760Ile (c.2280G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about DOCK1 p.Met760Ile (c.2280G>A)?

AlphaMissense predicts likely pathogenic (score 0.6169) — an in-silico prediction, not a clinical call.

DOCK1 p.Met760Ile

c.2280G>A · rs773612844 · VCV2602770

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6169 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6169	likely pathogenic
REVEL	0.133	moderately benign-leaning
SaProt	LLR -7.64	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 4.2	GERP 0.51, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 321 kb · p 0.017 · regional, not allelic
Overall
CADD	21.2	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 M739I vs ClinVar M760I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,886 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,704 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: DOCK1
Protein: p.Met760Ile
Coding: c.2280G>A
MANE Select: NM_001290223
dbSNP: rs773612844
Type: single nucleotide variant
Location: chr10:127052759 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.63 · 1 PDB

Full DOCK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOCK1 p.Met760Val Uncertain significance ★ ⚠ same residue
DOCK1 p.Pro1783Ser Uncertain significance ★★ ⚠ same type
DOCK1 p.Ala1185Thr Uncertain significance ★ ⚠ same type
DOCK1 p.Ala151Thr Uncertain significance ★ ⚠ same type
DOCK1 p.Ala1578Ser Uncertain significance ★ ⚠ same type
DOCK1 p.Ala1590Gly Uncertain significance ★ ⚠ same type
DOCK1 p.Ala1620Val Uncertain significance ★ ⚠ same type
DOCK1 p.Ala1689Ser Uncertain significance ★ ⚠ 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/dock1-p-met760ile (accessed [today's date]).

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