Is ERAP1 p.Val647Ile (c.1939G>A) pathogenic?

ERAP1 p.Val647Ile (c.1939G>A) is classified Benign in ERAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). AlphaMissense: likely benign (0.1871); Low-frequency (popmax 2.41%, mid).

How common is ERAP1 p.Val647Ile (c.1939G>A) in the general population?

ERAP1 p.Val647Ile (c.1939G>A) is low-frequency (popmax 2.41%, mid) (gnomAD).

What do computational predictors say about ERAP1 p.Val647Ile (c.1939G>A)?

AlphaMissense predicts likely benign (score 0.1871) — an in-silico prediction, not a clinical call.

ERAP1 p.Val647Ile

c.1939G>A · rs111363347 · VCV2655598

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1871 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.41%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1871	likely benign
REVEL	0.276	benign-leaning
SaProt	LLR -7.96	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 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.11 · regional, not allelic
Overall
CADD	24.9	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 2.41% Middle Eastern · 146/6,062 alleles

Filtering AF 2.09% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.97%

Overall 0.253% 4,083/1,614,058 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.41%	42
South Asian	1.47%	68
Remaining individualsnot grpmax-eligible	0.334%	299
Admixed American	0.217%	462
Ashkenazi Jewishnot grpmax-eligible	0.209%	478
European (non-Finnish)	0.183%	546
African / African-American	0.032%	3,126
Finnishnot grpmax-eligible	0.0125%	8,003
East Asian	0.00891%	11,220

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.Val647Ile
Coding: c.1939G>A
MANE Select: NM_001040458
dbSNP: rs111363347
Type: single nucleotide variant
Location: chr5:96785792 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.78 · 27 PDB
Residue 647: 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-val647ile (accessed [today's date]).

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