Is ERAP1 p.Phe674Ile (c.2020T>A) pathogenic?

ERAP1 p.Phe674Ile (c.2020T>A) is classified Uncertain significance in ERAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-23). AlphaMissense: likely benign (0.1622); Absent from gnomAD v4.1.

How common is ERAP1 p.Phe674Ile (c.2020T>A) in the general population?

ERAP1 p.Phe674Ile (c.2020T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERAP1 p.Phe674Ile (c.2020T>A)?

AlphaMissense predicts likely benign (score 0.1622) — an in-silico prediction, not a clinical call.

ERAP1 p.Phe674Ile

c.2020T>A · VCV4019126

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1622 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1622	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -4.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.32	acceptor loss, 7 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.11 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

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.Phe674Ile
Coding: c.2020T>A
MANE Select: NM_001040458
Type: single nucleotide variant
Location: chr5:96784004 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.78 · 27 PDB
Residue 674: 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-phe674ile (accessed [today's date]).

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