Is CDH26 p.Pro754Leu (c.2261C>T) pathogenic?

CDH26 p.Pro754Leu (c.2261C>T) is classified Likely benign in CDH26 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-21). AlphaMissense: likely benign (0.066); Ultra-rare (popmax 0.0164%, mid).

How common is CDH26 p.Pro754Leu (c.2261C>T) in the general population?

CDH26 p.Pro754Leu (c.2261C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CDH26 p.Pro754Leu (c.2261C>T)?

AlphaMissense predicts likely benign (score 0.066) — an in-silico prediction, not a clinical call.

CDH26 p.Pro754Leu

c.2261C>T · VCV4651157

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.066 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.066	likely benign
REVEL	0.188	benign-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.23	acceptor loss · deltas
Constraint at this position
Conservation	phyloP -6.1	GERP -2.1
Regional constraint	o/e 0.98	unconstrained · MANE · 54 kb · p 0.44 · regional, not allelic
Overall
CADD	0.136	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00248% 40/1,613,950 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0144%	6,942
African / African-American	0.00534%	18,723
East Asian	0.00223%	44,886
European (non-Finnish)	0.00203%	49,165
Admixed American	0.00167%	60,010

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.Pro754Leu
Coding: c.2261C>T
MANE Select: NM_177980
Type: single nucleotide variant
Location: chr20:60006753 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.84

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-pro754leu (accessed [today's date]).

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