Is DOK4 p.Pro39Leu (c.116C>T) pathogenic?

DOK4 p.Pro39Leu (c.116C>T) is classified Uncertain significance in DOK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely pathogenic (0.7266); Very rare (popmax 0.00102%, nfe).

How common is DOK4 p.Pro39Leu (c.116C>T) in the general population?

DOK4 p.Pro39Leu (c.116C>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about DOK4 p.Pro39Leu (c.116C>T)?

AlphaMissense predicts likely pathogenic (score 0.7266) — an in-silico prediction, not a clinical call.

DOK4 p.Pro39Leu

c.116C>T · VCV4014347

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7266 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7266	likely pathogenic
REVEL	0.443	indeterminate
SaProt	LLR -8.96	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 6,127 bp · p 0.03 · regional, not allelic
Overall
CADD	27.7	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 0.00102% European (non-Finnish) · 12/1,179,916 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000889% 13/1,461,688 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)grpmax	0.00102%	98,326

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro39Leu
Coding: c.116C>T
MANE Select: NM_018110
Type: single nucleotide variant
Location: chr16:57475908 (GRCh38)
Gene constraint: LOEUF 0.915 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.73
Residue 39: the ph domain

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-pro39leu (accessed [today's date]).

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