Is DHX9 p.Arg781Pro (c.2342G>C) pathogenic?

DHX9 p.Arg781Pro (c.2342G>C) is classified Uncertain significance in DHX9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-28). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1.

How common is DHX9 p.Arg781Pro (c.2342G>C) in the general population?

DHX9 p.Arg781Pro (c.2342G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DHX9 p.Arg781Pro (c.2342G>C)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

DHX9 p.Arg781Pro

c.2342G>C · VCV4082614

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic · top 2% in DHX9
REVEL	0.376	indeterminate
SaProt	LLR -16.88	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 1.8, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 5,101 bp · p 8e-23 · regional, not allelic
Overall
CADD	23.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DHX9
Protein: p.Arg781Pro
Coding: c.2342G>C
MANE Select: NM_001357
Type: single nucleotide variant
Location: chr1:182878164 (GRCh38)
Gene constraint: LOEUF 0.263 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.84 · 7 PDB
Residue 781: the 'necessary for interaction with h2ax' region; the 'core helicase' region; an α-helix; the helicase c-terminal domain; a UniProt-annotated variant site (in mrd75; likely pathogenic)

Full DHX9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DHX9 p.Ala355Thr Uncertain significance ★★ ⚠ same type
DHX9 p.Asn1133His Uncertain significance ★★ ⚠ same type
DHX9 p.Pro586Ala Uncertain significance ★★ ⚠ same type
DHX9 c.364+6G>T Benign ★★ same type
DHX9 p.Ile903= Benign ★★ same type
DHX9 p.Leu244= Benign ★★ same type
DHX9 p.Tyr875= Benign ★★ same type
DHX9 c.1141-1G>A Likely pathogenic ★ same type

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-arg781pro (accessed [today's date]).

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