Is DDX3X p.Phe84Cys (c.251T>G) pathogenic?

DDX3X p.Phe84Cys (c.251T>G) is classified Conflicting classifications of pathogenicity in DDX3X (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.2833); Very rare (popmax 0.00175%, afr); Associated with DDX3X-related disorder.

What condition is associated with DDX3X p.Phe84Cys (c.251T>G)?

DDX3X p.Phe84Cys (c.251T>G) is associated with DDX3X-related disorder (ClinVar).

How common is DDX3X p.Phe84Cys (c.251T>G) in the general population?

DDX3X p.Phe84Cys (c.251T>G) is very rare (popmax 0.00175%, afr) (gnomAD).

What do computational predictors say about DDX3X p.Phe84Cys (c.251T>G)?

AlphaMissense predicts likely benign (score 0.2833) — an in-silico prediction, not a clinical call.

DDX3X p.Phe84Cys

c.251T>G · rs892274119 · VCV1208727

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2833 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DDX3X-related disorder

Computational evidence

Protein change
AlphaMissense	0.2833	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -8.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 8,391 bp · p 0.0057 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00175% African / African-American · 1/57,177 alleles

Filtering AF 0.000385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.000744% 9/1,209,502 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00175%	57,177
European (non-Finnish)	0.000894%	111,835

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.Phe84Cys
Coding: c.251T>G
MANE Select: NM_001356
dbSNP: rs892274119
Type: single nucleotide variant
Location: chrX:41341583 (GRCh38)
Structure: AlphaFold pLDDT 73.24 · 17 PDB
Residue 84: the 'required for tbk1 and ikbke-dependent ifnb1 activation' region; the 'disordered' region; the 'interaction with vacv protein k7' region

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

Disease context

DDX3X-related disorder

Similar variants

DDX3X p.Phe84= Likely benign ★★ same residue
DDX3X p.Arg46Ter Pathogenic ★★ same condition
DDX3X p.Arg603Ter Pathogenic ★★ same condition
DDX3X p.Cys298Ter Pathogenic/Likely pathogenic ★★ same condition
DDX3X p.Ile514Thr Pathogenic/Likely pathogenic ★★ same condition
DDX3X p.Met1Ile Pathogenic ★★ same condition
DDX3X p.Pro41Ser Pathogenic/Likely pathogenic ★★ same condition
DDX3X p.Pro568Leu 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-phe84cys (accessed [today's date]).

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