Is CDHR2 p.Ile97Val (c.289A>G) pathogenic?

CDHR2 p.Ile97Val (c.289A>G) is classified Uncertain significance in CDHR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.0973); Ultra-rare (popmax 0.0736%, sas).

How common is CDHR2 p.Ile97Val (c.289A>G) in the general population?

CDHR2 p.Ile97Val (c.289A>G) is ultra-rare (popmax 0.0736%, sas) (gnomAD).

What do computational predictors say about CDHR2 p.Ile97Val (c.289A>G)?

AlphaMissense predicts likely benign (score 0.0973) — an in-silico prediction, not a clinical call.

CDHR2 p.Ile97Val

c.289A>G · rs144430304 · VCV2389543

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0973 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0736%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0973	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -3.92	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 2.5	GERP -0.075, phastCons 0.9
Regional constraint	o/e 0.93	unconstrained · MANE · 19 kb · p 0.025 · regional, not allelic
Overall
CADD	5.961	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 0.0736% South Asian · 67/91,082 alleles

Filtering AF 0.0695% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0679%

Overall 0.0628% 1,014/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0736%	1,359
European (non-Finnish)	0.0736%	1,359
Finnishnot grpmax-eligible	0.0437%	2,286
Remaining individualsnot grpmax-eligible	0.0352%	2,841
Middle Eastern	0.033%	3,031
African / African-American	0.0253%	3,950
Admixed American	0.0117%	8,573
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602

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.Ile97Val
Coding: c.289A>G
MANE Select: NM_017675
dbSNP: rs144430304
Type: single nucleotide variant
Location: chr5:176568984 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 2 PDB
Residue 97: the cadherin 1 domain; a β-strand

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

Similar variants

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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-ile97val (accessed [today's date]).

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