Is CDH5 p.Ser159Pro (c.475T>C) pathogenic?

CDH5 p.Ser159Pro (c.475T>C) is classified Uncertain significance in CDH5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-17). AlphaMissense: likely pathogenic (0.8065); Absent from gnomAD v4.1.

How common is CDH5 p.Ser159Pro (c.475T>C) in the general population?

CDH5 p.Ser159Pro (c.475T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH5 p.Ser159Pro (c.475T>C)?

AlphaMissense predicts likely pathogenic (score 0.8065) — an in-silico prediction, not a clinical call.

CDH5 p.Ser159Pro

c.475T>C · VCV3999043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8065 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8065	likely pathogenic
REVEL	0.341	indeterminate
SaProt	LLR -13.01	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP -1.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 24 kb · p 0.00013 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDH5
Protein: p.Ser159Pro
Coding: c.475T>C
MANE Select: NM_001795
Type: single nucleotide variant
Location: chr16:66387073 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.46
Residue 159: the cadherin 2 domain

Full CDH5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH5 p.Val266= Benign ★★ same type
CDH5 p.Ala13Ser Uncertain significance ★ ⚠ same type
CDH5 p.Ala187Val Uncertain significance ★ ⚠ same type
CDH5 p.Ala201Ser Uncertain significance ★ ⚠ same type
CDH5 p.Ala21Thr Uncertain significance ★ ⚠ same type
CDH5 p.Ala229Val Uncertain significance ★ ⚠ same type
CDH5 p.Ala353Val Uncertain significance ★ ⚠ same type
CDH5 p.Ala395Thr 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/cdh5-p-ser159pro (accessed [today's date]).

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