Is CDH7 p.Leu674Pro (c.2021T>C) pathogenic?

CDH7 p.Leu674Pro (c.2021T>C) is classified Uncertain significance in CDH7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely pathogenic (0.6683); Very rare (popmax 8.47e-05%, nfe).

How common is CDH7 p.Leu674Pro (c.2021T>C) in the general population?

CDH7 p.Leu674Pro (c.2021T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CDH7 p.Leu674Pro (c.2021T>C)?

AlphaMissense predicts likely pathogenic (score 0.6683) — an in-silico prediction, not a clinical call.

CDH7 p.Leu674Pro

c.2021T>C · VCV3999067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6683 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6683	likely pathogenic
REVEL	0.488	indeterminate
SaProt	LLR -2.98	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.12, phastCons 1
Overall
CADD	22.6	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 8.47e-05% European (non-Finnish) · 1/1,179,958 alleles

Overall 6.84e-05% 1/1,461,732 alleles · very rare

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: CDH7
Protein: p.Leu674Pro
Coding: c.2021T>C
MANE Select: NM_021153 · reported on NM_004361
Type: single nucleotide variant
Location: chr18:65880557 (GRCh38)
Structure: AlphaFold pLDDT 78.14

Full CDH7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH19 p.Pro558= Benign ★★ same type
CDH19 p.Thr89Ile Benign ★★ same type
CDH7 c.1612+22C>T Benign ★★ same type
CDH7 c.1612+24A>T Benign ★★ same type
CDH7 c.1612+81T>C Benign ★★ same type
CDH7 c.1864+225A>G Benign ★★ same type
CDH7 c.210+52G>A Benign ★★ same type
CDH7 c.210+56T>G Benign ★★ 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/cdh7-p-leu674pro (accessed [today's date]).

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