Is ERAP1 p.Met349Val (c.1045A>G) pathogenic?

ERAP1 p.Met349Val (c.1045A>G) is classified Benign in ERAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: likely benign (0.1389); Common (popmax 22.1%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ERAP1 p.Met349Val (c.1045A>G)?

AlphaMissense predicts likely benign (score 0.1389) — an in-silico prediction, not a clinical call.

ERAP1 p.Met349Val

Q: How common is ERAP1 p.Met349Val (c.1045A>G) in the general population?

ERAP1 p.Met349Val (c.1045A>G) is common (popmax 22.1%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1045A>G · rs2287987 · VCV2688496

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1389 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 22.1%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1389	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -6.49	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 2.8	GERP -0.17, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 10 kb · p 0.003 · regional, not allelic
Overall
CADD	17.79	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 22.1% European (non-Finnish) · 260,986/1,178,290 alleles

Filtering AF 22.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 22%

Overall 19.4% 313,271/1,612,274 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	22.1%	5
Finnishnot grpmax-eligible	19.5%	5
Remaining individualsnot grpmax-eligible	17.7%	6
Ashkenazi Jewishnot grpmax-eligible	12.7%	8
Amishnot grpmax-eligible	12.1%	8
Admixed American	10.5%	10
Middle Eastern	9.82%	10
South Asian	9.71%	10
African / African-American	9.54%	10
East Asian	4.55%	22

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.Met349Val
Coding: c.1045A>G
MANE Select: NM_001040458
dbSNP: rs2287987
Type: single nucleotide variant
Location: chr5:96793832 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.78 · 27 PDB
Residue 349: a UniProt-annotated variant site (in); 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-met349val (accessed [today's date]).

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