Is IDE p.Pro461Ser (c.1381C>T) pathogenic?

IDE p.Pro461Ser (c.1381C>T) is classified Uncertain significance in IDE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: ambiguous (0.3784); Ultra-rare (popmax 0.0123%, amr).

How common is IDE p.Pro461Ser (c.1381C>T) in the general population?

IDE p.Pro461Ser (c.1381C>T) is ultra-rare (popmax 0.0123%, amr) (gnomAD).

What do computational predictors say about IDE p.Pro461Ser (c.1381C>T)?

AlphaMissense predicts ambiguous (score 0.3784) — an in-silico prediction, not a clinical call.

IDE p.Pro461Ser

c.1381C>T · rs747481660 · VCV2297704

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3784 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3784	ambiguous
REVEL	0.284	benign-leaning
SaProt	LLR -10.04	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 0.87, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 56 kb · p 4.3e-15 · regional, not allelic
Overall
CADD	27.0	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 0.0123% Admixed American · 7/56,694 alleles

Filtering AF 0.00628% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00584%

Overall 0.00634% 101/1,593,050 alleles · ultra-rare exomes 94/1,440,950 · genomes 7/152,100 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0123%	8,099
European (non-Finnish)	0.00761%	13,143
Remaining individualsnot grpmax-eligible	0.00649%	15,413
African / African-American	0.00136%	73,700

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.Pro461Ser
Coding: c.1381C>T
MANE Select: NM_004969
dbSNP: rs747481660
Type: single nucleotide variant
Location: chr10:92504843 (GRCh38)
Gene constraint: LOEUF 0.638 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 94.06 · 62 PDB
Residue 461: an α-helix

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

Similar variants

IDE p.Pro461Ala Uncertain significance ★ ⚠ same residue
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

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-pro461ser (accessed [today's date]).

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