Is DDX3X p.Ser543Pro (c.1627T>C) pathogenic?

DDX3X p.Ser543Pro (c.1627T>C) is classified Likely pathogenic in DDX3X (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-11). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with intellectual disability, X-linked 102.

What condition is associated with DDX3X p.Ser543Pro (c.1627T>C)?

DDX3X p.Ser543Pro (c.1627T>C) is associated with intellectual disability, X-linked 102 (ClinVar).

How common is DDX3X p.Ser543Pro (c.1627T>C) in the general population?

DDX3X p.Ser543Pro (c.1627T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DDX3X p.Ser543Pro (c.1627T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

DDX3X p.Ser543Pro

c.1627T>C · VCV4056415

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, X-linked 102

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic ✓ concordant with ClinVar · top 8% in DDX3X
REVEL	0.702	pathogenic-leaning
SaProt	LLR -11.18	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 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 312 bp · p 3.3e-07 · regional, not allelic
Overall
CADD	25.8	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

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: DDX3X
Protein: p.Ser543Pro
Coding: c.1627T>C
MANE Select: NM_001356
Type: single nucleotide variant
Location: chrX:41346870 (GRCh38)
Structure: AlphaFold pLDDT 73.24 · 17 PDB
Residue 543: the 'interaction with hcv core protein' region; the 'interaction with nxf1' region; a β-strand; the helicase c-terminal domain; a modified residue (phosphoserine; by csnk1e and tbk1; in vitro); the 'interaction with gsk3b' 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.Ser543Leu Uncertain significance ★ ⚠ same residue
DDX3X p.Ser543Ter 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-ser543pro (accessed [today's date]).

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