Is CDHR1 p.Pro590Ser (c.1768C>T) pathogenic?

CDHR1 p.Pro590Ser (c.1768C>T) is classified Uncertain significance in CDHR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-21). AlphaMissense: likely benign (0.143); Very rare (popmax 0.00668%, afr).

How common is CDHR1 p.Pro590Ser (c.1768C>T) in the general population?

CDHR1 p.Pro590Ser (c.1768C>T) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about CDHR1 p.Pro590Ser (c.1768C>T)?

AlphaMissense predicts likely benign (score 0.143) — an in-silico prediction, not a clinical call.

CDHR1 p.Pro590Ser

c.1768C>T · rs866406140 · VCV959629

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.143 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.143	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -8.26	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 0.026	GERP 3.4, phastCons 0.091
Regional constraint	o/e 1.06	unconstrained · MANE · 20 kb · p 0.035 · regional, not allelic
Overall
CADD	22.0	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 0.00668% African / African-American · 5/74,904 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00031% 5/1,613,952 alleles · very rare

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.Pro590Ser
Coding: c.1768C>T
MANE Select: NM_033100
dbSNP: rs866406140
Type: single nucleotide variant
Location: chr10:84212393 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.79
Residue 590: the cadherin 6 domain

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

Similar variants

CDHR1 p.Pro590= Likely benign ★ same residue
CDHR1 c.1168-1G>C Pathogenic/Likely pathogenic ★★ same type
CDHR1 c.1321-1G>A Likely pathogenic ★★ same type
CDHR1 c.1485+2T>C Pathogenic ★★ same type
CDHR1 c.1485+2T>G Pathogenic ★★ same type
CDHR1 c.1554-2A>C Pathogenic/Likely pathogenic ★★ same type
CDHR1 c.297+1G>T Pathogenic ★★ same type
CDHR1 c.525+1G>A Pathogenic ★★ 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/cdhr1-p-pro590ser (accessed [today's date]).

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