Is DOK4 p.Pro266Leu (c.797C>T) pathogenic?

DOK4 p.Pro266Leu (c.797C>T) is classified Uncertain significance in DOK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely pathogenic (0.9945); Very rare (popmax 0.00549%, sas).

How common is DOK4 p.Pro266Leu (c.797C>T) in the general population?

DOK4 p.Pro266Leu (c.797C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about DOK4 p.Pro266Leu (c.797C>T)?

AlphaMissense predicts likely pathogenic (score 0.9945) — an in-silico prediction, not a clinical call.

DOK4 p.Pro266Leu

c.797C>T · rs370144496 · VCV2241518

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9945 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9945	likely pathogenic
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -7.70	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 6,127 bp · p 0.03 · regional, not allelic
Overall
CADD	32.0	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 0.00549% South Asian · 5/91,084 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000743% 12/1,614,092 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,217
Admixed American	0.00167%	60,006
European (non-Finnish)	0.000508%	196,672

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: DOK4
Protein: p.Pro266Leu
Coding: c.797C>T
MANE Select: NM_018110
dbSNP: rs370144496
Type: single nucleotide variant
Location: chr16:57473678 (GRCh38)
Gene constraint: LOEUF 0.915 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.73

Full DOK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOK4 p.Glu74Asp Benign ★★ same type
DOK4 p.Ala191Thr Uncertain significance ★ ⚠ same type
DOK4 p.Ala204Thr Uncertain significance ★ ⚠ same type
DOK4 p.Ala229Ser Uncertain significance ★ ⚠ same type
DOK4 p.Ala294Gly Uncertain significance ★ ⚠ same type
DOK4 p.Ala294Pro Uncertain significance ★ ⚠ same type
DOK4 p.Arg115Cys Uncertain significance ★ ⚠ same type
DOK4 p.Arg138Cys 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/dok4-p-pro266leu (accessed [today's date]).

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