Is CDH16 p.Pro277Leu (c.830C>T) pathogenic?

CDH16 p.Pro277Leu (c.830C>T) is classified Likely benign in CDH16 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-04). AlphaMissense: likely benign (0.0723); Ultra-rare (popmax 0.02%, amr).

How common is CDH16 p.Pro277Leu (c.830C>T) in the general population?

CDH16 p.Pro277Leu (c.830C>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about CDH16 p.Pro277Leu (c.830C>T)?

AlphaMissense predicts likely benign (score 0.0723) — an in-silico prediction, not a clinical call.

CDH16 p.Pro277Leu

c.830C>T · rs140723714 · VCV2354566

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0723 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0723	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -8.53	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 0.91	GERP -2.1, phastCons 0.35
Regional constraint	o/e 1.05	unconstrained · MANE · 9,670 bp · p 0.11 · regional, not allelic
Overall
CADD	3.083	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 0.02% Admixed American · 12/59,998 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00452% 73/1,613,926 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,000
Middle Eastern	0.0165%	6,078
Remaining individualsnot grpmax-eligible	0.0064%	15,620
African / African-American	0.00534%	18,728
European (non-Finnish)	0.00441%	22,692

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: CDH16
Protein: p.Pro277Leu
Coding: c.830C>T
MANE Select: NM_004062
dbSNP: rs140723714
Type: single nucleotide variant
Location: chr16:66913564 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.17
Residue 277: the cadherin 3 domain

Full CDH16 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH16 p.Arg717His Benign ★★ same type
CDH16 p.Leu377= Benign ★★ same type
CDH16 p.Ala133Ser Uncertain significance ★ ⚠ same type
CDH16 p.Ala159Val Uncertain significance ★ ⚠ same type
CDH16 p.Ala173Thr Uncertain significance ★ ⚠ same type
CDH16 p.Ala202Val Uncertain significance ★ ⚠ same type
CDH16 p.Ala20Thr Uncertain significance ★ ⚠ same type
CDH16 p.Ala23Thr 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/cdh16-p-pro277leu (accessed [today's date]).

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