Is IDE p.Phe275Leu (c.825T>G) pathogenic?

IDE p.Phe275Leu (c.825T>G) is classified Uncertain significance in IDE (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-27). AlphaMissense: likely pathogenic (0.9703); Very rare (popmax 0.000341%, nfe).

How common is IDE p.Phe275Leu (c.825T>G) in the general population?

IDE p.Phe275Leu (c.825T>G) is very rare (popmax 0.000341%, nfe) (gnomAD).

What do computational predictors say about IDE p.Phe275Leu (c.825T>G)?

AlphaMissense predicts likely pathogenic (score 0.9703) — an in-silico prediction, not a clinical call.

IDE p.Phe275Leu

c.825T>G · rs767688483 · VCV2339482

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000341%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9703	likely pathogenic
REVEL	0.453	indeterminate
SaProt	LLR -10.91	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 64 kb · p 0.32 · regional, not allelic
Overall
CADD	24.9	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 0.000341% European (non-Finnish) · 4/1,171,774 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000276% 4/1,451,336 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: IDE
Protein: p.Phe275Leu
Coding: c.825T>G
MANE Select: NM_004969
dbSNP: rs767688483
Type: single nucleotide variant
Location: chr10:92510122 (GRCh38)
Gene constraint: LOEUF 0.638 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 62 PDB
Residue 275: an α-helix

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-phe275leu (accessed [today's date]).

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