Is DDX59 p.Pro445Ser (c.1333C>T) pathogenic?

DDX59 p.Pro445Ser (c.1333C>T) is classified Uncertain significance in DDX59 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-17). AlphaMissense: ambiguous (0.4223); Ultra-rare (popmax 0.0167%, mid); Associated with Inborn genetic diseases.

What condition is associated with DDX59 p.Pro445Ser (c.1333C>T)?

DDX59 p.Pro445Ser (c.1333C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DDX59 p.Pro445Ser (c.1333C>T) in the general population?

DDX59 p.Pro445Ser (c.1333C>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about DDX59 p.Pro445Ser (c.1333C>T)?

AlphaMissense predicts ambiguous (score 0.4223) — an in-silico prediction, not a clinical call.

DDX59 p.Pro445Ser

c.1333C>T · VCV4010520

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4223 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4223	ambiguous
REVEL	0.471	indeterminate
SaProt	LLR -9.72	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 22 kb · p 0.03 · regional, not allelic
Overall
CADD	24.7	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 0.0167% Middle Eastern · 1/5,982 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000255% 4/1,568,268 alleles · ultra-rare exomes 3/1,416,200 · genomes 1/152,068 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,982
European (non-Finnish)	0.000257%	388,688

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: DDX59
Protein: p.Pro445Ser
Coding: c.1333C>T
MANE Select: NM_001031725
Type: single nucleotide variant
Location: chr1:200649208 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.71 · 1 PDB
Residue 445: the helicase c-terminal domain

Full DDX59 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DDX59 p.Pro445Leu Uncertain significance ★ same residue
DDX59 p.Arg318His Uncertain significance ★★ ⚠ same condition
DDX59 p.Glu179Gly Uncertain significance ★★ ⚠ same condition
DDX59 p.Glu30Lys Uncertain significance ★★ ⚠ same condition
DDX59 p.His400Gln Uncertain significance ★★ ⚠ same condition
DDX59 p.Ile609Asn Uncertain significance ★★ ⚠ same condition
DDX59 p.Ile9Met Uncertain significance ★★ ⚠ same condition
DDX59 p.Ala50Pro Likely benign ★★ 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/ddx59-p-pro445ser (accessed [today's date]).

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