Is CDX4 p.Arg177His (c.530G>A) pathogenic?

CDX4 p.Arg177His (c.530G>A) is classified Uncertain significance in CDX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-15). AlphaMissense: likely pathogenic (0.795); Very rare (popmax 0.00223%, amr).

How common is CDX4 p.Arg177His (c.530G>A) in the general population?

CDX4 p.Arg177His (c.530G>A) is very rare (popmax 0.00223%, amr) (gnomAD).

What do computational predictors say about CDX4 p.Arg177His (c.530G>A)?

AlphaMissense predicts likely pathogenic (score 0.795) — an in-silico prediction, not a clinical call.

CDX4 p.Arg177His

c.530G>A · VCV3489808

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.795 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.795	likely pathogenic
REVEL	0.978	strongly pathogenic-leaning
SaProt	LLR -14.44	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 2.4	GERP 1.7, phastCons 0.99
Regional constraint	o/e 1.08	unconstrained · MANE · 7,328 bp · p 0.2 · regional, not allelic
Overall
CADD	23.8	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 0.00223% Admixed American · 1/44,879 alleles

Filtering AF 0.00126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00167% 20/1,199,908 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00223%	44,879
European (non-Finnish)	0.00202%	49,396
African / African-American	0.00177%	56,615

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.Arg177His
Coding: c.530G>A
MANE Select: NM_005193
Type: single nucleotide variant
Location: chrX:73453544 (GRCh38)
Structure: AlphaFold pLDDT 63.87
Residue 177: 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.Arg215Lys Uncertain significance ★ ⚠ same type
CDX4 p.Arg215Thr Uncertain significance ★ ⚠ same type
CDX4 p.Arg270Cys Uncertain significance ★ ⚠ same type
CDX4 p.Asp182Gly 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-arg177his (accessed [today's date]).

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