Is ERAP2 p.Arg205His (c.614G>A) pathogenic?

ERAP2 p.Arg205His (c.614G>A) is classified Uncertain significance in ERAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely pathogenic (0.5849); Ultra-rare (popmax 0.0814%, afr).

How common is ERAP2 p.Arg205His (c.614G>A) in the general population?

ERAP2 p.Arg205His (c.614G>A) is ultra-rare (popmax 0.0814%, afr) (gnomAD).

What do computational predictors say about ERAP2 p.Arg205His (c.614G>A)?

AlphaMissense predicts likely pathogenic (score 0.5849) — an in-silico prediction, not a clinical call.

ERAP2 p.Arg205His

c.614G>A · rs73150323 · VCV2464505

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5849 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0814%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5849	likely pathogenic
REVEL	0.314	indeterminate
SaProt	LLR -10.15	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.48	GERP -0.49
Regional constraint	o/e 0.99	unconstrained · MANE · 30 kb · p 0.75 · regional, not allelic
Overall
CADD	23.2	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 0.0814% African / African-American · 61/74,966 alleles

Filtering AF 0.0649% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0591%

Overall 0.00626% 101/1,613,276 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0814%	1,229
Admixed American	0.0217%	4,603
Remaining individualsnot grpmax-eligible	0.0096%	10,414
South Asian	0.0088%	11,358
Finnishnot grpmax-eligible	0.00156%	64,004
European (non-Finnish)	0.00102%	98,311

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: ERAP2
Protein: p.Arg205His
Coding: c.614G>A
MANE Select: NM_001040458 · reported on NM_022350
dbSNP: rs73150323
Type: single nucleotide variant
Location: chr5:96883830 (GRCh38)

Full ERAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/erap2-p-arg205his (accessed [today's date]).

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