Is CDX1 p.Ser22Ile (c.65G>T) pathogenic?

CDX1 p.Ser22Ile (c.65G>T) is classified Uncertain significance in CDX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely benign (0.2923); Very rare (popmax 0.00106%, nfe).

How common is CDX1 p.Ser22Ile (c.65G>T) in the general population?

CDX1 p.Ser22Ile (c.65G>T) is very rare (popmax 0.00106%, nfe) (gnomAD).

What do computational predictors say about CDX1 p.Ser22Ile (c.65G>T)?

AlphaMissense predicts likely benign (score 0.2923) — an in-silico prediction, not a clinical call.

CDX1 p.Ser22Ile

c.65G>T · VCV4651696

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00106%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2923	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -10.20	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 17 kb · p 0.73 · regional, not allelic
Overall
CADD	20.5	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 0.00106% European (non-Finnish) · 12/1,132,760 alleles

Filtering AF 0.000565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000446%

Overall 0.000888% 12/1,351,646 alleles · very rare

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: CDX1
Protein: p.Ser22Ile
Coding: c.65G>T
MANE Select: NM_001804
Type: single nucleotide variant
Location: chr5:150166941 (GRCh38)
Gene constraint: LOEUF 1.625 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.02 · 2 PDB
Residue 22: the 'disordered' region

Full CDX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDX1 p.Gly143Arg Uncertain significance ★★ ⚠ same type
CDX1 p.Ala21Val Uncertain significance ★ ⚠ same type
CDX1 p.Ala38Pro Uncertain significance ★ ⚠ same type
CDX1 p.Ala60Val Uncertain significance ★ ⚠ same type
CDX1 p.Ala63Pro Uncertain significance ★ ⚠ same type
CDX1 p.Ala82Val Uncertain significance ★ ⚠ same type
CDX1 p.Arg137Leu Uncertain significance ★ ⚠ same type
CDX1 p.Arg152Trp 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/cdx1-p-ser22ile (accessed [today's date]).

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