Is CDH24 p.Ile556Thr (c.1667T>C) pathogenic?

CDH24 p.Ile556Thr (c.1667T>C) is classified Uncertain significance in CDH24 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-06). AlphaMissense: likely pathogenic (0.6845); Very rare (popmax 0.000862%, nfe).

How common is CDH24 p.Ile556Thr (c.1667T>C) in the general population?

CDH24 p.Ile556Thr (c.1667T>C) is very rare (popmax 0.000862%, nfe) (gnomAD).

What do computational predictors say about CDH24 p.Ile556Thr (c.1667T>C)?

AlphaMissense predicts likely pathogenic (score 0.6845) — an in-silico prediction, not a clinical call.

CDH24 p.Ile556Thr

c.1667T>C · rs774772546 · VCV2333503

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6845 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000862%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6845	likely pathogenic
REVEL	0.245	benign-leaning
SaProt	LLR -11.69	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 6,685 bp · p 9e-07 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I594T vs ClinVar I556T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000862% European (non-Finnish) · 10/1,159,602 alleles

Filtering AF 0.000436% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000318%

Overall 0.000703% 10/1,422,806 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: CDH24
Protein: p.Ile556Thr
Coding: c.1667T>C
MANE Select: NM_144985
dbSNP: rs774772546
Type: single nucleotide variant
Location: chr14:23049206 (GRCh38)
Gene constraint: LOEUF 1.146 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.54
Residue 556: the cadherin 5 domain

Full CDH24 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH24 c.1363+390G>A Uncertain significance ★ ⚠ same type
CDH24 c.1363+418G>T Uncertain significance ★ ⚠ same type
CDH24 c.1363+470A>G Uncertain significance ★ ⚠ same type
CDH24 c.1363+476G>A Uncertain significance ★ ⚠ same type
CDH24 c.1363+476G>T Uncertain significance ★ ⚠ same type
CDH24 c.1363+486C>T Uncertain significance ★ ⚠ same type
CDH24 p.Ala119Val Uncertain significance ★ ⚠ same type
CDH24 p.Ala174Val 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/cdh24-p-ile556thr (accessed [today's date]).

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