Is CDX4 p.Pro40Thr (c.118C>A) pathogenic?

CDX4 p.Pro40Thr (c.118C>A) is classified Conflicting classifications of pathogenicity in CDX4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-14). AlphaMissense: likely benign (0.0781); Ultra-rare (popmax 0.0109%, amr).

How common is CDX4 p.Pro40Thr (c.118C>A) in the general population?

CDX4 p.Pro40Thr (c.118C>A) is ultra-rare (popmax 0.0109%, amr) (gnomAD).

What do computational predictors say about CDX4 p.Pro40Thr (c.118C>A)?

AlphaMissense predicts likely benign (score 0.0781) — an in-silico prediction, not a clinical call.

CDX4 p.Pro40Thr

c.118C>A · rs774580628 · VCV2464621

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0781 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0781	likely benign
REVEL	0.311	indeterminate
SaProt	LLR -6.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 7,328 bp · p 0.2 · regional, not allelic
Overall
CADD	16.03	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 0.0109% Admixed American · 5/45,683 alleles

Filtering AF 0.00551% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00501%

Overall 0.00587% 71/1,208,619 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0109%	9,137
European (non-Finnish)	0.00693%	14,430
Remaining individualsnot grpmax-eligible	0.00631%	15,848
African / African-American	0.00176%	56,904

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.Pro40Thr
Coding: c.118C>A
MANE Select: NM_005193
dbSNP: rs774580628
Type: single nucleotide variant
Location: chrX:73447371 (GRCh38)
Structure: AlphaFold pLDDT 63.87
Residue 40: the 'disordered' 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-pro40thr (accessed [today's date]).

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