Is ERAP1 p.Met447Val (c.1339A>G) pathogenic?

ERAP1 p.Met447Val (c.1339A>G) is classified Uncertain significance in ERAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-20). AlphaMissense: likely pathogenic (0.6348); Ultra-rare (popmax 0.02%, afr).

How common is ERAP1 p.Met447Val (c.1339A>G) in the general population?

ERAP1 p.Met447Val (c.1339A>G) is ultra-rare (popmax 0.02%, afr) (gnomAD).

What do computational predictors say about ERAP1 p.Met447Val (c.1339A>G)?

AlphaMissense predicts likely pathogenic (score 0.6348) — an in-silico prediction, not a clinical call.

ERAP1 p.Met447Val

c.1339A>G · rs184320964 · VCV3090032

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6348 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6348	likely pathogenic
REVEL	0.716	pathogenic-leaning
SaProt	LLR -13.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.11 · regional, not allelic
Overall
CADD	26.3	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 0.02% African / African-American · 15/74,974 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00988%

Overall 0.0018% 29/1,608,820 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.02%	4,998
South Asian	0.00879%	11,372
Admixed American	0.00333%	30,009
Remaining individualsnot grpmax-eligible	0.0016%	62,322
European (non-Finnish)	0.000255%	391,701

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.Met447Val
Coding: c.1339A>G
MANE Select: NM_001040458
dbSNP: rs184320964
Type: single nucleotide variant
Location: chr5:96790625 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.78 · 27 PDB
Residue 447: 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-met447val (accessed [today's date]).

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