Is CDHR2 p.Pro693Thr (c.2077C>A) pathogenic?

CDHR2 p.Pro693Thr (c.2077C>A) is classified Uncertain significance in CDHR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely pathogenic (0.9432); Absent from gnomAD v4.1.

How common is CDHR2 p.Pro693Thr (c.2077C>A) in the general population?

CDHR2 p.Pro693Thr (c.2077C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDHR2 p.Pro693Thr (c.2077C>A)?

AlphaMissense predicts likely pathogenic (score 0.9432) — an in-silico prediction, not a clinical call.

CDHR2 p.Pro693Thr

c.2077C>A · VCV4224061

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9432 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9432	likely pathogenic · top 5% in CDHR2
REVEL	0.81	moderately pathogenic-leaning
SaProt	LLR -14.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 19 kb · p 0.025 · regional, not allelic
Overall
CADD	26.7	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: CDHR2
Protein: p.Pro693Thr
Coding: c.2077C>A
MANE Select: NM_017675
Type: single nucleotide variant
Location: chr5:176584208 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 2 PDB
Residue 693: 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-pro693thr (accessed [today's date]).

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