Is CDHR4 p.Leu372Val (c.1114C>G) pathogenic?

CDHR4 p.Leu372Val (c.1114C>G) is classified Uncertain significance in CDHR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-28). AlphaMissense: likely benign (0.1168); Very rare (popmax 0.00148%, nfe).

How common is CDHR4 p.Leu372Val (c.1114C>G) in the general population?

CDHR4 p.Leu372Val (c.1114C>G) is very rare (popmax 0.00148%, nfe) (gnomAD).

What do computational predictors say about CDHR4 p.Leu372Val (c.1114C>G)?

AlphaMissense predicts likely benign (score 0.1168) — an in-silico prediction, not a clinical call.

CDHR4 p.Leu372Val

c.1114C>G · rs2544885628 · VCV2541641

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1168 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00148%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1168	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -11.72	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -0.89, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 8,977 bp · p 0.0033 · regional, not allelic
Overall
CADD	20.3	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 0.00148% European (non-Finnish) · 17/1,146,990 alleles

Filtering AF 0.000903% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000738%

Overall 0.00121% 17/1,399,398 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: CDHR4
Protein: p.Leu372Val
Coding: c.1114C>G
MANE Select: NM_001007540
dbSNP: rs2544885628
Type: single nucleotide variant
Location: chr3:49795018 (GRCh38)
Gene constraint: LOEUF 1.174 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.90
Residue 372: the cadherin 2 domain

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

Similar variants

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
CDHR4 p.Ala456Pro 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-leu372val (accessed [today's date]).

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