Is CDHR4 p.Leu499Phe (c.1495C>T) pathogenic?

CDHR4 p.Leu499Phe (c.1495C>T) is classified Uncertain significance in CDHR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: likely benign (0.2655); Absent from gnomAD v4.1.

How common is CDHR4 p.Leu499Phe (c.1495C>T) in the general population?

CDHR4 p.Leu499Phe (c.1495C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDHR4 p.Leu499Phe (c.1495C>T)?

AlphaMissense predicts likely benign (score 0.2655) — an in-silico prediction, not a clinical call.

CDHR4 p.Leu499Phe

c.1495C>T · VCV4224116

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2655 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2655	likely benign
REVEL	0.384	indeterminate
SaProt	LLR -13.12	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 0.33, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 8,977 bp · p 0.0033 · regional, not allelic
Overall
CADD	24.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDHR4
Protein: p.Leu499Phe
Coding: c.1495C>T
MANE Select: NM_001007540
Type: single nucleotide variant
Location: chr3:49793711 (GRCh38)
Gene constraint: LOEUF 1.174 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.90
Residue 499: the cadherin 3 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-leu499phe (accessed [today's date]).

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