Is CDX4 p.Cys194Arg (c.580T>C) pathogenic?

CDX4 p.Cys194Arg (c.580T>C) is classified Uncertain significance in CDX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-21). AlphaMissense: ambiguous (0.4156); Ultra-rare (popmax 0.0327%, eas).

How common is CDX4 p.Cys194Arg (c.580T>C) in the general population?

CDX4 p.Cys194Arg (c.580T>C) is ultra-rare (popmax 0.0327%, eas) (gnomAD).

What do computational predictors say about CDX4 p.Cys194Arg (c.580T>C)?

AlphaMissense predicts ambiguous (score 0.4156) — an in-silico prediction, not a clinical call.

CDX4 p.Cys194Arg

c.580T>C · rs750645875 · VCV2279285

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4156 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0327%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4156	ambiguous
REVEL	0.706	pathogenic-leaning
SaProt	LLR -6.98	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 7,328 bp · p 0.2 · regional, not allelic
Overall
CADD	22.6	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 0.0327% East Asian · 11/33,595 alleles

Filtering AF 0.0183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.001% 12/1,199,440 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0327%	3,054
Admixed American	0.00222%	44,962

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: CDX4
Protein: p.Cys194Arg
Coding: c.580T>C
MANE Select: NM_005193
dbSNP: rs750645875
Type: single nucleotide variant
Location: chrX:73453594 (GRCh38)
Structure: AlphaFold pLDDT 63.87
Residue 194: a DNA-binding region

Full CDX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDX4 p.Ala106Ser Uncertain significance ★ ⚠ same type
CDX4 p.Ala207Thr Uncertain significance ★ ⚠ same type
CDX4 p.Ala226Gly Uncertain significance ★ ⚠ same type
CDX4 p.Arg161Gly Uncertain significance ★ ⚠ same type
CDX4 p.Arg177His Uncertain significance ★ ⚠ same type
CDX4 p.Arg215Lys Uncertain significance ★ ⚠ same type
CDX4 p.Arg215Thr Uncertain significance ★ ⚠ same type
CDX4 p.Arg270Cys Uncertain significance ★ ⚠ 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/cdx4-p-cys194arg (accessed [today's date]).

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