Is DHX9 p.Pro586Ala (c.1756C>G) pathogenic?

DHX9 p.Pro586Ala (c.1756C>G) is classified Uncertain significance in DHX9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-01). AlphaMissense: likely benign (0.2051); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DHX9 p.Pro586Ala (c.1756C>G)?

DHX9 p.Pro586Ala (c.1756C>G) is associated with Inborn genetic diseases (ClinVar).

How common is DHX9 p.Pro586Ala (c.1756C>G) in the general population?

DHX9 p.Pro586Ala (c.1756C>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about DHX9 p.Pro586Ala (c.1756C>G)?

AlphaMissense predicts likely benign (score 0.2051) — an in-silico prediction, not a clinical call.

DHX9 p.Pro586Ala

c.1756C>G · VCV3769940

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2051 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2051	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -6.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 4,180 bp · p 1.3e-09 · regional, not allelic
Overall
CADD	23.6	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 0.00017% European (non-Finnish) · 2/1,179,534 alleles

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

Overall 0.000124% 2/1,613,074 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: DHX9
Protein: p.Pro586Ala
Coding: c.1756C>G
MANE Select: NM_001357
Type: single nucleotide variant
Location: chr1:182874895 (GRCh38)
Gene constraint: LOEUF 0.263 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.84 · 7 PDB
Residue 586: the 'necessary for interaction with rna polymerase ii holoenzyme' region; the 'necessary for interaction with h2ax' region; the 'core helicase' region; a UniProt-annotated variant site (in mrd75; likely pathogenic)

Full DHX9 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

DHX9 p.Arg1052Ter Pathogenic ★ same condition
DHX9 p.Arg764Ter Pathogenic ★ same condition
DHX9 p.Arg767Ter Pathogenic ★ same condition
DHX9 p.Tyr568Ter Pathogenic ★ same condition
DHX9 c.3260+5G>A Uncertain significance ★ same condition
DHX9 p.Ala1106Thr Uncertain significance ★ ⚠ same condition
DHX9 p.Ala1165Thr Uncertain significance ★ ⚠ same condition
DHX9 p.Ala1203Thr Uncertain significance ★ ⚠ 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/dhx9-p-pro586ala (accessed [today's date]).

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