Is CDHR2 p.Leu657Pro (c.1970T>C) pathogenic?

CDHR2 p.Leu657Pro (c.1970T>C) is classified Uncertain significance in CDHR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: ambiguous (0.4299); Very rare (popmax 8.47e-05%, nfe).

How common is CDHR2 p.Leu657Pro (c.1970T>C) in the general population?

CDHR2 p.Leu657Pro (c.1970T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CDHR2 p.Leu657Pro (c.1970T>C)?

AlphaMissense predicts ambiguous (score 0.4299) — an in-silico prediction, not a clinical call.

CDHR2 p.Leu657Pro

c.1970T>C · VCV3830251

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4299 · ACMG-weighted

gnomAD v4.1

Rare

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

Computational evidence

Protein change
AlphaMissense	0.4299	ambiguous
REVEL	0.418	indeterminate
SaProt	LLR -11.24	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 0.65, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 19 kb · p 0.025 · regional, not allelic
Overall
CADD	23.7	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) · 1/1,180,034 alleles

Overall 6.84e-05% 1/1,461,820 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: CDHR2
Protein: p.Leu657Pro
Coding: c.1970T>C
MANE Select: NM_017675
Type: single nucleotide variant
Location: chr5:176581494 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 2 PDB
Residue 657: the cadherin 6 domain

Full CDHR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDHR2 p.Ala1162Thr Uncertain significance ★ ⚠ same type
CDHR2 p.Ala121Thr Uncertain significance ★ ⚠ same type
CDHR2 p.Ala13Val Uncertain significance ★ ⚠ same type
CDHR2 p.Ala415Thr Uncertain significance ★ ⚠ same type
CDHR2 p.Ala423Thr Uncertain significance ★ ⚠ same type
CDHR2 p.Ala512Thr Uncertain significance ★ ⚠ same type
CDHR2 p.Ala652Thr Uncertain significance ★ ⚠ same type
CDHR2 p.Ala656Thr 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/cdhr2-p-leu657pro (accessed [today's date]).

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