Is CDHR1 p.Val559Ile (c.1675G>A) pathogenic?

CDHR1 p.Val559Ile (c.1675G>A) is classified Conflicting classifications of pathogenicity in CDHR1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-20). AlphaMissense: likely benign (0.0715); Ultra-rare (popmax 0.0111%, eas); Associated with Inborn genetic diseases.

What condition is associated with CDHR1 p.Val559Ile (c.1675G>A)?

CDHR1 p.Val559Ile (c.1675G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CDHR1 p.Val559Ile (c.1675G>A) in the general population?

CDHR1 p.Val559Ile (c.1675G>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about CDHR1 p.Val559Ile (c.1675G>A)?

AlphaMissense predicts likely benign (score 0.0715) — an in-silico prediction, not a clinical call.

CDHR1 p.Val559Ile

c.1675G>A · rs778340853 · VCV1517610

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0715 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0715	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -6.61	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 0.054	GERP -1.4, phastCons 0.83
Regional constraint	o/e 1.06	unconstrained · MANE · 20 kb · p 0.035 · regional, not allelic
Overall
CADD	4.474	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 0.0111% East Asian · 5/44,886 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00254% 41/1,614,210 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,977
Admixed American	0.00833%	12,007
Finnishnot grpmax-eligible	0.00625%	16,009
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
African / African-American	0.00266%	37,524
European (non-Finnish)	0.00195%	51,306
Remaining individualsnot grpmax-eligible	0.0016%	62,506

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: CDHR1
Protein: p.Val559Ile
Coding: c.1675G>A
MANE Select: NM_033100
dbSNP: rs778340853
Type: single nucleotide variant
Location: chr10:84212300 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.79
Residue 559: the cadherin 5 domain

Full CDHR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDHR1 p.Ala106Thr Uncertain significance ★★ ⚠ same condition
CDHR1 p.Ala10Val Uncertain significance ★★ ⚠ same condition
CDHR1 p.Ala118Asp Uncertain significance ★★ ⚠ same condition
CDHR1 p.Ala132Val Uncertain significance ★★ ⚠ same condition
CDHR1 p.Ala292Asp Uncertain significance ★★ ⚠ same condition
CDHR1 p.Ala393Gly Uncertain significance ★★ ⚠ same condition
CDHR1 p.Ala493Val Uncertain significance ★★ ⚠ same condition
CDHR1 p.Ala793Thr Uncertain significance ★★ ⚠ same condition

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/cdhr1-p-val559ile (accessed [today's date]).

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