Is DDX41 p.Arg255His (c.764G>A) pathogenic?

DDX41 p.Arg255His (c.764G>A) is classified Uncertain significance in DDX41 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-10). AlphaMissense: likely benign (0.1224); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with DDX41 p.Arg255His (c.764G>A)?

DDX41 p.Arg255His (c.764G>A) is associated with Inborn genetic diseases, DDX41-related hematologic malignancy predisposition syndrome (ClinVar).

How common is DDX41 p.Arg255His (c.764G>A) in the general population?

DDX41 p.Arg255His (c.764G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about DDX41 p.Arg255His (c.764G>A)?

AlphaMissense predicts likely benign (score 0.1224) — an in-silico prediction, not a clinical call.

DDX41 p.Arg255His

c.764G>A · rs775735135 · VCV2505028

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1224 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1224	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -2.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,281 bp · p 0.16 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,918 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000744% 12/1,612,320 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,730
East Asian	0.00223%	44,854
South Asian	0.0022%	45,538
Admixed American	0.00167%	59,988
European (non-Finnish)	0.000339%	294,707

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.Arg255His
Coding: c.764G>A
MANE Select: NM_016222
dbSNP: rs775735135
Type: single nucleotide variant
Location: chr5:177514950 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.38 · 5 PDB
Residue 255: the helicase atp-binding domain

Full DDX41 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

Also linked: DDX41-related hematologic malignancy predisposition syndrome

Similar variants

DDX41 p.Arg255Cys Uncertain significance ★★ ⚠ same residue
DDX41 p.Arg255= Likely benign ★★ same residue
DDX41 c.1303-2A>G Likely pathogenic ★★ same condition
DDX41 c.27+1G>A Likely pathogenic ★★ same condition
DDX41 c.434+1G>A Pathogenic/Likely pathogenic ★★ same condition
DDX41 c.434+1G>C Pathogenic/Likely pathogenic ★★ same condition
DDX41 c.571+1G>A Likely pathogenic ★★ same condition
DDX41 c.572-1G>A Pathogenic/Likely 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-arg255his (accessed [today's date]).

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