Is DOK4 p.Asp118Ala (c.353A>C) pathogenic?

DOK4 p.Asp118Ala (c.353A>C) is classified Uncertain significance in DOK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: ambiguous (0.4041); Ultra-rare (popmax 0.012%, afr).

How common is DOK4 p.Asp118Ala (c.353A>C) in the general population?

DOK4 p.Asp118Ala (c.353A>C) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about DOK4 p.Asp118Ala (c.353A>C)?

AlphaMissense predicts ambiguous (score 0.4041) — an in-silico prediction, not a clinical call.

DOK4 p.Asp118Ala

c.353A>C · VCV4014351

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4041 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4041	ambiguous
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -10.75	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 6,127 bp · p 0.03 · regional, not allelic
Overall
CADD	27.5	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 0.012% African / African-American · 9/74,838 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.000682% 11/1,613,830 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,315
Admixed American	0.00333%	29,993

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.Asp118Ala
Coding: c.353A>C
MANE Select: NM_018110
Type: single nucleotide variant
Location: chr16:57475156 (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.Asp118Asn Uncertain significance ★ ⚠ same residue
DOK4 p.Asp118Val Uncertain significance ★ ⚠ same residue
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

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-asp118ala (accessed [today's date]).

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