Is CDHR4 p.Arg652Gln (c.1955G>A) pathogenic?

CDHR4 p.Arg652Gln (c.1955G>A) is classified Uncertain significance in CDHR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: likely benign (0.0655); Ultra-rare (popmax 0.0167%, mid).

How common is CDHR4 p.Arg652Gln (c.1955G>A) in the general population?

CDHR4 p.Arg652Gln (c.1955G>A) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about CDHR4 p.Arg652Gln (c.1955G>A)?

AlphaMissense predicts likely benign (score 0.0655) — an in-silico prediction, not a clinical call.

CDHR4 p.Arg652Gln

c.1955G>A · VCV3999153

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0655 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0655	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -5.41	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 1.1	GERP -2.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 8,977 bp · p 0.0033 · regional, not allelic
Overall
CADD	14.9	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 0.0167% Middle Eastern · 1/5,992 alleles

Filtering AF 0.00447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00315%

Overall 0.00174% 27/1,549,468 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0201%	4,987
Middle Easterngrpmax	0.0167%	5,992
African / African-American	0.00959%	10,427
Admixed American	0.00196%	50,932
South Asian	0.00119%	83,952
European (non-Finnish)	0.000437%	229,084

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CDHR4
Protein: p.Arg652Gln
Coding: c.1955G>A
MANE Select: NM_001007540
Type: single nucleotide variant
Location: chr3:49792894 (GRCh38)
Gene constraint: LOEUF 1.174 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.90
Residue 652: the cadherin 4 domain

Full CDHR4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDHR4 p.Arg652Trp Likely benign ★ same residue
CDHR4 p.Ala12Val Uncertain significance ★ ⚠ same type
CDHR4 p.Ala149Val Uncertain significance ★ ⚠ same type
CDHR4 p.Ala302Val Uncertain significance ★ ⚠ same type
CDHR4 p.Ala310Pro Uncertain significance ★ ⚠ same type
CDHR4 p.Ala318Asp Uncertain significance ★ ⚠ same type
CDHR4 p.Ala341Pro Uncertain significance ★ ⚠ same type
CDHR4 p.Ala385Gly 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/cdhr4-p-arg652gln (accessed [today's date]).

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