Is IDE p.Leu450Pro (c.1349T>C) pathogenic?

IDE p.Leu450Pro (c.1349T>C) is classified Uncertain significance in IDE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-15). AlphaMissense: likely pathogenic (0.9794); Very rare (popmax 0.00341%, nfe).

How common is IDE p.Leu450Pro (c.1349T>C) in the general population?

IDE p.Leu450Pro (c.1349T>C) is very rare (popmax 0.00341%, nfe) (gnomAD).

What do computational predictors say about IDE p.Leu450Pro (c.1349T>C)?

AlphaMissense predicts likely pathogenic (score 0.9794) — an in-silico prediction, not a clinical call.

IDE p.Leu450Pro

c.1349T>C · VCV3527486

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9794 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00341%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9794	likely pathogenic
REVEL	0.692	pathogenic-leaning
SaProt	LLR -13.94	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 56 kb · p 4.3e-15 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00341% European (non-Finnish) · 39/1,142,126 alleles

Filtering AF 0.00256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00224%

Overall 0.0027% 42/1,556,806 alleles · very rare exomes 40/1,404,600 · genomes 2/152,206 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00341%	29,285
Remaining individualsnot grpmax-eligible	0.00331%	30,219
African / African-American	0.00138%	72,666

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: IDE
Protein: p.Leu450Pro
Coding: c.1349T>C
MANE Select: NM_004969
Type: single nucleotide variant
Location: chr10:92504875 (GRCh38)
Gene constraint: LOEUF 0.638 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 62 PDB
Residue 450: a turn

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

Similar variants

IDE p.Asn841= Benign ★★ same type
IDE p.His10= Benign/Likely benign ★★ same type
IDE p.Ile791= Benign ★★ same type
IDE p.Ala185Glu Uncertain significance ★ ⚠ same type
IDE p.Ala452Thr Uncertain significance ★ ⚠ same type
IDE p.Ala479Thr Uncertain significance ★ ⚠ same type
IDE p.Ala544Val Uncertain significance ★ ⚠ same type
IDE p.Ala610Val 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/ide-p-leu450pro (accessed [today's date]).

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