Is CDHR2 p.Ala869Val (c.2606C>T) pathogenic?

CDHR2 p.Ala869Val (c.2606C>T) is classified Likely benign in CDHR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). AlphaMissense: likely benign (0.0991); Ultra-rare (popmax 0.0132%, sas).

How common is CDHR2 p.Ala869Val (c.2606C>T) in the general population?

CDHR2 p.Ala869Val (c.2606C>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about CDHR2 p.Ala869Val (c.2606C>T)?

AlphaMissense predicts likely benign (score 0.0991) — an in-silico prediction, not a clinical call.

CDHR2 p.Ala869Val

c.2606C>T · VCV4224039

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0991 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0991	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -9.20	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 -3.6	GERP -3
Regional constraint	o/e 0.28	constrained · MANE · 54 bp · p 0.00027 · regional, not allelic
Overall
CADD	0.002	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 0.0132% South Asian · 12/91,032 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00211% 34/1,613,808 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,586
African / African-American	0.00666%	15,009
Admixed American	0.005%	19,991
Remaining individualsnot grpmax-eligible	0.0032%	31,238
East Asian	0.00223%	44,852
European (non-Finnish)	0.000932%	107,261

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.Ala869Val
Coding: c.2606C>T
MANE Select: NM_017675
Type: single nucleotide variant
Location: chr5:176584887 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 2 PDB
Residue 869: the cadherin 8 domain

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

Similar variants

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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-ala869val (accessed [today's date]).

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