Is DDX41 p.Pro510Ser (c.1528C>T) pathogenic?

DDX41 p.Pro510Ser (c.1528C>T) is classified Uncertain significance in DDX41 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-09). AlphaMissense: likely pathogenic (0.9925); Very rare (popmax 0.00814%, nfe); Associated with DDX41-related hematologic malignancy predisposition syndrome.

What condition is associated with DDX41 p.Pro510Ser (c.1528C>T)?

DDX41 p.Pro510Ser (c.1528C>T) is associated with DDX41-related hematologic malignancy predisposition syndrome (ClinVar).

How common is DDX41 p.Pro510Ser (c.1528C>T) in the general population?

DDX41 p.Pro510Ser (c.1528C>T) is very rare (popmax 0.00814%, nfe) (gnomAD).

What do computational predictors say about DDX41 p.Pro510Ser (c.1528C>T)?

AlphaMissense predicts likely pathogenic (score 0.9925) — an in-silico prediction, not a clinical call.

DDX41 p.Pro510Ser

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.1528C>T · rs199756165 · VCV1981975

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00814%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DDX41-related hematologic malignancy predisposition syndrome

Computational evidence

Protein change
AlphaMissense	0.9925	likely pathogenic
REVEL	0.801	moderately pathogenic-leaning
SaProt	LLR -10.12	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 1,932 bp · p 1.8e-21 · regional, not allelic
Overall
CADD	29.3	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 0.00814% European (non-Finnish) · 96/1,180,014 alleles

Filtering AF 0.00681% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00675% 109/1,614,016 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0144%	6,943
European (non-Finnish)grpmax	0.00814%	12,292
Finnishnot grpmax-eligible	0.00625%	16,009

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro510Ser
Coding: c.1528C>T
MANE Select: NM_016222
dbSNP: rs199756165
Type: single nucleotide variant
Location: chr5:177512517 (GRCh38)
Gene constraint: LOEUF 0.768 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.38 · 5 PDB
Residue 510: the helicase c-terminal 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.Pro510= 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
DDX41 p.Arg369Ter Pathogenic/Likely pathogenic ★★ same condition
DDX41 p.Gln370Ter 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-pro510ser (accessed [today's date]).

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