Is CDHR2 p.Ile291Val (c.871A>G) pathogenic?

CDHR2 p.Ile291Val (c.871A>G) is classified Uncertain significance in CDHR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-30). AlphaMissense: likely benign (0.085); Very rare (popmax 0.00231%, sas).

How common is CDHR2 p.Ile291Val (c.871A>G) in the general population?

CDHR2 p.Ile291Val (c.871A>G) is very rare (popmax 0.00231%, sas) (gnomAD).

What do computational predictors say about CDHR2 p.Ile291Val (c.871A>G)?

AlphaMissense predicts likely benign (score 0.085) — an in-silico prediction, not a clinical call.

CDHR2 p.Ile291Val

c.871A>G · VCV3830250

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.085 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00231%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.085	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -8.05	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	GERP 1.4, phastCons 0.96
Regional constraint	o/e 0.93	unconstrained · MANE · 19 kb · p 0.025 · regional, not allelic
Overall
CADD	13.24	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 0.00231% South Asian · 2/86,640 alleles

Filtering AF 0.000383% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000143%

Overall 0.000382% 6/1,570,128 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00231%	43,320
European (non-Finnish)	0.000346%	289,250

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.Ile291Val
Coding: c.871A>G
MANE Select: NM_017675
Type: single nucleotide variant
Location: chr5:176575750 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 2 PDB
Residue 291: the cadherin 3 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-ile291val (accessed [today's date]).

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