Is ERAP1 p.Ala637= (c.1911G>A) pathogenic?

ERAP1 p.Ala637= (c.1911G>A) is classified Benign in ERAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). Common (popmax 57.7%, afr) — too common for a highly-penetrant pathogenic allele.

ERAP1 p.Ala637=

Q: How common is ERAP1 p.Ala637= (c.1911G>A) in the general population?

ERAP1 p.Ala637= (c.1911G>A) is common (popmax 57.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1911G>A · rs469783 · VCV2688369

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 57.7%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.20	donor gain · deltas
Constraint at this position
Conservation	phyloP -2	GERP -4.1
Overall
CADD	11.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 57.7% African / African-American · 43,215/74,918 alleles

Filtering AF 57.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 57.3%

Overall 56.6% 913,251/1,613,624 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	57.8%	2
African / African-Americangrpmax	57.7%	2
European (non-Finnish)	57.4%	2
Admixed American	56.8%	2
Remaining individualsnot grpmax-eligible	54.7%	2
South Asian	52.8%	2
East Asian	51.4%	2
Ashkenazi Jewishnot grpmax-eligible	44.6%	2
Middle Eastern	42%	2
Amishnot grpmax-eligible	35.9%	3

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala637=
Coding: c.1911G>A
MANE Select: NM_001040458
dbSNP: rs469783
Type: single nucleotide variant
Location: chr5:96785820 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.78 · 27 PDB
Residue 637: 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-ala637 (accessed [today's date]).

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