Is DDX3X p.Pro41His (c.122C>A) pathogenic?

DDX3X p.Pro41His (c.122C>A) is classified Uncertain significance in DDX3X (ClinVar, Single submitter, 1 submitter; last evaluated 2017-01-13). AlphaMissense: likely pathogenic (0.9972); Very rare (popmax 0.000122%, nfe); Associated with intellectual disability, X-linked 102.

What condition is associated with DDX3X p.Pro41His (c.122C>A)?

DDX3X p.Pro41His (c.122C>A) is associated with intellectual disability, X-linked 102 (ClinVar).

How common is DDX3X p.Pro41His (c.122C>A) in the general population?

DDX3X p.Pro41His (c.122C>A) is very rare (popmax 0.000122%, nfe) (gnomAD).

What do computational predictors say about DDX3X p.Pro41His (c.122C>A)?

AlphaMissense predicts likely pathogenic (score 0.9972) — an in-silico prediction, not a clinical call.

DDX3X p.Pro41His

c.122C>A · rs1341824034 · VCV975950

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000122%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability, X-linked 102

Computational evidence

Protein change
AlphaMissense	0.9972	likely pathogenic
REVEL	0.368	indeterminate
SaProt	LLR -13.94	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 5.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 8,391 bp · p 0.0057 · regional, not allelic
Overall
CADD	24.9	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 0.000122% European (non-Finnish) · 1/817,474 alleles

Overall 0.000103% 1/966,225 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: DDX3X
Protein: p.Pro41His
Coding: c.122C>A
MANE Select: NM_001356
dbSNP: rs1341824034
Type: single nucleotide variant
Location: chrX:41339054 (GRCh38)
Structure: AlphaFold pLDDT 73.24 · 17 PDB
Residue 41: the 'required for tbk1 and ikbke-dependent ifnb1 activation' region; the 'disordered' region; the 'interaction with eif4e' region

Full DDX3X gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, X-linked 102 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DDX3X p.Pro41Ser Pathogenic/Likely pathogenic ★★ same residue
DDX3X p.Pro41del Pathogenic/Likely pathogenic ★★ same residue
DDX3X c.1497+1G>A Likely pathogenic ★★ same condition
DDX3X c.865-1G>A Pathogenic ★★ same condition
DDX3X c.865-2A>G Pathogenic ★★ same condition
DDX3X p.Ala349Thr Pathogenic/Likely pathogenic ★★ same condition
DDX3X p.Ala497Val Pathogenic/Likely pathogenic ★★ same condition
DDX3X p.Arg292Ter 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/ddx3x-p-pro41his (accessed [today's date]).

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