Is CDH6 p.Pro517Ser (c.1549C>T) pathogenic?

CDH6 p.Pro517Ser (c.1549C>T) is classified Uncertain significance in CDH6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-22). AlphaMissense: likely benign (0.1048); Absent from gnomAD v4.1.

How common is CDH6 p.Pro517Ser (c.1549C>T) in the general population?

CDH6 p.Pro517Ser (c.1549C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH6 p.Pro517Ser (c.1549C>T)?

AlphaMissense predicts likely benign (score 0.1048) — an in-silico prediction, not a clinical call.

CDH6 p.Pro517Ser

c.1549C>T · rs2546663301 · VCV2528460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1048 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1048	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -5.55	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 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 50 kb · p 7.7e-20 · regional, not allelic
Overall
CADD	21.9	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.

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: CDH6
Protein: p.Pro517Ser
Coding: c.1549C>T
MANE Select: NM_004932
dbSNP: rs2546663301
Type: single nucleotide variant
Location: chr5:31317411 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 78.67 · 1 PDB
Residue 517: the cadherin 5 domain

Full CDH6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH6 p.Ala130Val Uncertain significance ★ ⚠ same type
CDH6 p.Ala489Ser Uncertain significance ★ ⚠ same type
CDH6 p.Ala634Gly Uncertain significance ★ ⚠ same type
CDH6 p.Ala671Ser Uncertain significance ★ ⚠ same type
CDH6 p.Ala706Val Uncertain significance ★ ⚠ same type
CDH6 p.Ala729Val Uncertain significance ★ ⚠ same type
CDH6 p.Ala739Val Uncertain significance ★ ⚠ same type
CDH6 p.Arg115Lys 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/cdh6-p-pro517ser (accessed [today's date]).

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