Is DDX41 p.Arg323Ser (c.967C>A) pathogenic?

DDX41 p.Arg323Ser (c.967C>A) is classified Uncertain significance in DDX41 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-10). AlphaMissense: likely pathogenic (0.9996); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DDX41 p.Arg323Ser (c.967C>A)?

DDX41 p.Arg323Ser (c.967C>A) is associated with Inborn genetic diseases (ClinVar).

How common is DDX41 p.Arg323Ser (c.967C>A) in the general population?

DDX41 p.Arg323Ser (c.967C>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about DDX41 p.Arg323Ser (c.967C>A)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

DDX41 p.Arg323Ser

c.967C>A · VCV3668378

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 4% in DDX41
REVEL	0.489	indeterminate
SaProt	LLR -14.97	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 9.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,281 bp · p 0.16 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000169% European (non-Finnish) · 2/1,180,000 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,432 alleles · very rare

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.Arg323Ser
Coding: c.967C>A
MANE Select: NM_016222
Type: single nucleotide variant
Location: chr5:177513816 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.38 · 5 PDB
Residue 323: the helicase atp-binding domain; an α-helix

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

Similar variants

DDX41 p.Arg323His Conflicting classifications of pathogenicity ★ ⚠ same residue
DDX41 p.Arg323= Likely benign ★ same residue
DDX41 p.Arg323Cys Uncertain significance ★ ⚠ same residue
DDX41 c.1303-2A>G Likely pathogenic ★★ same condition
DDX41 c.27+1G>A 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-arg323ser (accessed [today's date]).

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