Is CDH24 p.Leu765Arg (c.2294T>G) pathogenic?

CDH24 p.Leu765Arg (c.2294T>G) is classified Uncertain significance in CDH24 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). AlphaMissense: likely benign (0.3179); Very rare (popmax 0.00263%, sas).

How common is CDH24 p.Leu765Arg (c.2294T>G) in the general population?

CDH24 p.Leu765Arg (c.2294T>G) is very rare (popmax 0.00263%, sas) (gnomAD).

What do computational predictors say about CDH24 p.Leu765Arg (c.2294T>G)?

AlphaMissense predicts likely benign (score 0.3179) — an in-silico prediction, not a clinical call.

CDH24 p.Leu765Arg

c.2294T>G · VCV4651135

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3179 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3179	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR 2.13	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 6.8	GERP -3.5, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,064 bp · p 0.3 · regional, not allelic
Overall
CADD	19.41	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L803R vs ClinVar L765R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00263% South Asian · 2/76,074 alleles

Filtering AF 0.000436% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000163%

Overall 0.000154% 2/1,296,308 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.Leu765Arg
Coding: c.2294T>G
MANE Select: NM_144985
Type: single nucleotide variant
Location: chr14:23048032 (GRCh38)
Gene constraint: LOEUF 1.146 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.54

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-leu765arg (accessed [today's date]).

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