Is ERAP1 p.Leu763Pro (c.2288T>C) pathogenic?

ERAP1 p.Leu763Pro (c.2288T>C) is classified Uncertain significance in ERAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-01). AlphaMissense: ambiguous (0.4042); Absent from gnomAD v4.1.

How common is ERAP1 p.Leu763Pro (c.2288T>C) in the general population?

ERAP1 p.Leu763Pro (c.2288T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERAP1 p.Leu763Pro (c.2288T>C)?

AlphaMissense predicts ambiguous (score 0.4042) — an in-silico prediction, not a clinical call.

ERAP1 p.Leu763Pro

c.2288T>C · VCV3276165

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4042 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.4042	ambiguous
REVEL	0.463	indeterminate
SaProt	LLR -12.96	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.11 · regional, not allelic
Overall
CADD	23.6	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: ERAP1
Protein: p.Leu763Pro
Coding: c.2288T>C
MANE Select: NM_001040458
Type: single nucleotide variant
Location: chr5:96781852 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.78 · 27 PDB
Residue 763: an α-helix

Full ERAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERAP1 p.Ala356= Benign ★★ same type
ERAP1 p.Gly514Arg Benign/Likely benign ★★ same type
ERAP1 p.Ile915Thr Likely benign ★★ ⚠ same type
ERAP1 p.Ser18= Benign/Likely benign ★★ same type
ERAP1 p.Tyr57= Benign/Likely benign ★★ same type
ERAP1 p.Tyr789= Benign ★★ same type
ERAP2 p.Leu411Arg Benign/Likely benign ★★ ⚠ same type
CAST p.Leu618Phe 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/erap1-p-leu763pro (accessed [today's date]).

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