Is ERAP1 p.Pro557Leu (c.1670C>T) pathogenic?

ERAP1 p.Pro557Leu (c.1670C>T) is classified Uncertain significance in ERAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0678); Very rare (popmax 0.00891%, eas).

How common is ERAP1 p.Pro557Leu (c.1670C>T) in the general population?

ERAP1 p.Pro557Leu (c.1670C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about ERAP1 p.Pro557Leu (c.1670C>T)?

AlphaMissense predicts likely benign (score 0.0678) — an in-silico prediction, not a clinical call.

ERAP1 p.Pro557Leu

c.1670C>T · VCV4831925

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0678 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0678	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -6.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.77	GERP 1.1
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.11 · regional, not allelic
Overall
CADD	12.81	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

Grpmax group 0.00891% East Asian · 4/44,884 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000743% 12/1,614,136 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,221
African / African-American	0.004%	25,014
South Asian	0.00329%	30,357
Finnishnot grpmax-eligible	0.00156%	64,000
European (non-Finnish)	8.47e-05%	1,180,043

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: ERAP1
Protein: p.Pro557Leu
Coding: c.1670C>T
MANE Select: NM_001040458
Type: single nucleotide variant
Location: chr5:96788540 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.78 · 27 PDB

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-pro557leu (accessed [today's date]).

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