Is CDX2 p.Pro309Thr (c.925C>A) pathogenic?

CDX2 p.Pro309Thr (c.925C>A) is classified Uncertain significance in CDX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely benign (0.12); Very rare (popmax 0.00133%, afr).

How common is CDX2 p.Pro309Thr (c.925C>A) in the general population?

CDX2 p.Pro309Thr (c.925C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CDX2 p.Pro309Thr (c.925C>A)?

AlphaMissense predicts likely benign (score 0.12) — an in-silico prediction, not a clinical call.

CDX2 p.Pro309Thr

c.925C>A · VCV4224908

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.12 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.12	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -4.79	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 3.8	GERP -1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 146 bp · p 0.86 · regional, not allelic
Overall
CADD	19.27	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00133% African / African-American · 1/74,990 alleles

Overall 0.000137% 2/1,461,418 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,990
European (non-Finnish)	8.48e-05%	1,179,750

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: CDX2
Protein: p.Pro309Thr
Coding: c.925C>A
MANE Select: NM_001265
Type: single nucleotide variant
Location: chr13:27963132 (GRCh38)
Gene constraint: LOEUF 0.609 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 63.77 · 4 PDB
Residue 309: the 'disordered' region

Full CDX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDX2 p.Ter314Arg Likely pathogenic ★ same type
CDX2 p.Ala103Ser Uncertain significance ★ ⚠ same type
CDX2 p.Ala127Asp Uncertain significance ★ ⚠ same type
CDX2 p.Ala148Ser Uncertain significance ★ ⚠ same type
CDX2 p.Ala46Glu Uncertain significance ★ ⚠ same type
CDX2 p.Ala68Gly Uncertain significance ★ ⚠ same type
CDX2 p.Ala86Ser Uncertain significance ★ ⚠ same type
CDX2 p.Ala88Ser 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/cdx2-p-pro309thr (accessed [today's date]).

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