Is CDH26 p.Pro253Leu (c.758C>T) pathogenic?

CDH26 p.Pro253Leu (c.758C>T) is classified Uncertain significance in CDH26 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: likely benign (0.2038); Very rare (popmax 0.00534%, nfe).

How common is CDH26 p.Pro253Leu (c.758C>T) in the general population?

CDH26 p.Pro253Leu (c.758C>T) is very rare (popmax 0.00534%, nfe) (gnomAD).

What do computational predictors say about CDH26 p.Pro253Leu (c.758C>T)?

AlphaMissense predicts likely benign (score 0.2038) — an in-silico prediction, not a clinical call.

CDH26 p.Pro253Leu

c.758C>T · VCV3488942

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2038 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2038	likely benign
REVEL	0.209	benign-leaning
SaProt	LLR -11.25	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 0.82	GERP -0.83, phastCons 0.041
Regional constraint	o/e 0.98	unconstrained · MANE · 54 kb · p 0.44 · regional, not allelic
Overall
CADD	21.9	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 0.00534% European (non-Finnish) · 63/1,179,926 alleles

Filtering AF 0.00426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.00428% 69/1,613,822 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00534%	18,729
African / African-American	0.00401%	24,954
Admixed American	0.00167%	59,994
Remaining individualsnot grpmax-eligible	0.0016%	62,478
South Asian	0.0011%	91,060

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: CDH26
Protein: p.Pro253Leu
Coding: c.758C>T
MANE Select: NM_177980
Type: single nucleotide variant
Location: chr20:59985050 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.84
Residue 253: the cadherin 2 domain

Full CDH26 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH26 p.Ala189Gly Uncertain significance ★ ⚠ same type
CDH26 p.Ala238Thr Uncertain significance ★ ⚠ same type
CDH26 p.Ala274Glu Uncertain significance ★ ⚠ same type
CDH26 p.Ala308Ser Uncertain significance ★ ⚠ same type
CDH26 p.Ala390Thr Uncertain significance ★ ⚠ same type
CDH26 p.Ala598Gly Uncertain significance ★ ⚠ same type
CDH26 p.Ala617Asp Uncertain significance ★ ⚠ same type
CDH26 p.Ala617Pro 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/cdh26-p-pro253leu (accessed [today's date]).

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