Is CDHR5 p.Arg334His (c.1001G>A) pathogenic?

CDHR5 p.Arg334His (c.1001G>A) is classified Uncertain significance in CDHR5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-15). AlphaMissense: likely benign (0.2327); Rare (popmax 0.114%, afr).

How common is CDHR5 p.Arg334His (c.1001G>A) in the general population?

CDHR5 p.Arg334His (c.1001G>A) is rare (popmax 0.114%, afr) (gnomAD).

What do computational predictors say about CDHR5 p.Arg334His (c.1001G>A)?

AlphaMissense predicts likely benign (score 0.2327) — an in-silico prediction, not a clinical call.

CDHR5 p.Arg334His

c.1001G>A · VCV3265394

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2327 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.114%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2327	likely benign
REVEL	0.334	indeterminate
SaProt	LLR -0.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.51 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.11	GERP -0.7, phastCons 0.004
Regional constraint	o/e 1.11	unconstrained · MANE · 7,548 bp · p 0.00028 · regional, not allelic
Overall
CADD	22.6	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 0.114% African / African-American · 84/73,730 alleles

Filtering AF 0.0942% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.087%

Overall 0.00677% 105/1,551,744 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.114%	878
Remaining individualsnot grpmax-eligible	0.0116%	8,627
South Asian	0.00586%	17,067
Admixed American	0.00383%	26,120
European (non-Finnish)	0.000607%	164,632

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: CDHR5
Protein: p.Arg334His
Coding: c.1001G>A
MANE Select: NM_021924
Type: single nucleotide variant
Location: chr11:619859 (GRCh38)
Gene constraint: LOEUF 1.479 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.84 · 1 PDB
Residue 334: the cadherin 3 domain

Full CDHR5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDHR5 p.Arg334Cys Uncertain significance ★ ⚠ same residue
CDHR5 p.Arg182His Benign ★★ same type
CDHR5 p.Gly298= Benign ★★ same type
CDHR5 p.Ala151Pro Uncertain significance ★ ⚠ same type
CDHR5 p.Ala171Thr Uncertain significance ★ ⚠ same type
CDHR5 p.Ala230Thr Uncertain significance ★ ⚠ same type
CDHR5 p.Ala347Val Uncertain significance ★ ⚠ same type
CDHR5 p.Ala364Val 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/cdhr5-p-arg334his (accessed [today's date]).

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