Is CDHR2 p.Arg759Gln (c.2276G>A) pathogenic?

CDHR2 p.Arg759Gln (c.2276G>A) is classified Uncertain significance in CDHR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.0677); Ultra-rare (popmax 0.048%, afr).

How common is CDHR2 p.Arg759Gln (c.2276G>A) in the general population?

CDHR2 p.Arg759Gln (c.2276G>A) is ultra-rare (popmax 0.048%, afr) (gnomAD).

What do computational predictors say about CDHR2 p.Arg759Gln (c.2276G>A)?

AlphaMissense predicts likely benign (score 0.0677) — an in-silico prediction, not a clinical call.

CDHR2 p.Arg759Gln

c.2276G>A · rs143101284 · VCV2405884

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0677 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.048%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0677	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -5.29	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 -0.93	GERP -2.8
Regional constraint	o/e 0.93	unconstrained · MANE · 19 kb · p 0.025 · regional, not allelic
Overall
CADD	5.43	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

Grpmax group 0.048% African / African-American · 36/75,032 alleles

Filtering AF 0.0356% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00292% 47/1,612,080 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.048%	2,084
Remaining individualsnot grpmax-eligible	0.0032%	31,204
Admixed American	0.00167%	59,894
South Asian	0.0011%	90,794
European (non-Finnish)	0.000594%	168,401

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.Arg759Gln
Coding: c.2276G>A
MANE Select: NM_017675
dbSNP: rs143101284
Type: single nucleotide variant
Location: chr5:176584557 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 2 PDB
Residue 759: the cadherin 7 domain

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

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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-arg759gln (accessed [today's date]).

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