Is CDH24 p.Pro686Ser (c.2056C>T) pathogenic?

CDH24 p.Pro686Ser (c.2056C>T) is classified Uncertain significance in CDH24 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: likely benign (0.1513); Ultra-rare (popmax 0.0224%, sas).

How common is CDH24 p.Pro686Ser (c.2056C>T) in the general population?

CDH24 p.Pro686Ser (c.2056C>T) is ultra-rare (popmax 0.0224%, sas) (gnomAD).

What do computational predictors say about CDH24 p.Pro686Ser (c.2056C>T)?

AlphaMissense predicts likely benign (score 0.1513) — an in-silico prediction, not a clinical call.

CDH24 p.Pro686Ser

c.2056C>T · rs749727483 · VCV3141234

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1513 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0224%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1513	likely benign
REVEL	0.423	indeterminate
SaProt	LLR -7.92	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 9.3	GERP 1.8, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,064 bp · p 0.3 · regional, not allelic
Overall
CADD	21.1	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 P724S vs ClinVar P686S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0224% South Asian · 19/84,868 alleles

Filtering AF 0.0146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0122%

Overall 0.00169% 26/1,536,208 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0224%	4,467
Finnishnot grpmax-eligible	0.00184%	54,218
Remaining individualsnot grpmax-eligible	0.00171%	58,550
African / African-American	0.00144%	69,494
European (non-Finnish)	0.000348%	287,378

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.Pro686Ser
Coding: c.2056C>T
MANE Select: NM_144985
dbSNP: rs749727483
Type: single nucleotide variant
Location: chr14:23048270 (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-pro686ser (accessed [today's date]).

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