Is DDX41 p.Arg339Cys (c.1015C>T) pathogenic?

DDX41 p.Arg339Cys (c.1015C>T) is classified Conflicting classifications of pathogenicity in DDX41 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-15). AlphaMissense: likely pathogenic (0.6968); Very rare (popmax 0.01%, amr); Associated with DDX41-related hematologic malignancy predisposition syndrome.

What condition is associated with DDX41 p.Arg339Cys (c.1015C>T)?

DDX41 p.Arg339Cys (c.1015C>T) is associated with DDX41-related hematologic malignancy predisposition syndrome (ClinVar).

How common is DDX41 p.Arg339Cys (c.1015C>T) in the general population?

DDX41 p.Arg339Cys (c.1015C>T) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about DDX41 p.Arg339Cys (c.1015C>T)?

AlphaMissense predicts likely pathogenic (score 0.6968) — an in-silico prediction, not a clinical call.

DDX41 p.Arg339Cys

Q: How is DDX41-related hematologic malignancy predisposition syndrome inherited?

Typically Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

c.1015C>T · rs759862062 · VCV2136166

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6968 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

DDX41-related hematologic malignancy predisposition syndrome

Computational evidence

Protein change
AlphaMissense	0.6968	likely pathogenic
REVEL	0.328	indeterminate
SaProt	LLR -13.24	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,281 bp · p 0.16 · 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 0.01% Admixed American · 6/60,020 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00103% 15/1,461,598 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,003
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)	0.000678%	147,502

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: DDX41
Protein: p.Arg339Cys
Coding: c.1015C>T
MANE Select: NM_016222
dbSNP: rs759862062
Type: single nucleotide variant
Location: chr5:177513768 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.38 · 5 PDB
Residue 339: the helicase atp-binding domain

Full DDX41 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DDX41-related hematologic malignancy predisposition syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For DDX41-related hematologic malignancy predisposition syndrome (Orphanet):

Inheritance: Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

DDX41 p.Arg339Leu Likely pathogenic ★ same residue
DDX41 p.Arg339His Conflicting classifications of pathogenicity ★ ⚠ same residue
DDX41 p.Arg339= Likely benign ★ same residue
DDX41 c.434+1G>A Pathogenic/Likely pathogenic ★★ same condition
DDX41 c.434+1G>C Pathogenic/Likely pathogenic ★★ same condition
DDX41 c.935+1G>T Likely pathogenic ★★ same condition
DDX41 p.Arg159Ter Pathogenic ★★ same condition
DDX41 p.Arg311Ter Pathogenic ★★ 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/ddx41-p-arg339cys (accessed [today's date]).

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