Is ERAP1 p.Thr12Ile (c.35C>T) pathogenic?

ERAP1 p.Thr12Ile (c.35C>T) is classified Benign in ERAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: likely benign (0.0997); Common (popmax 13.1%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ERAP1 p.Thr12Ile (c.35C>T)?

AlphaMissense predicts likely benign (score 0.0997) — an in-silico prediction, not a clinical call.

ERAP1 p.Thr12Ile

Q: How common is ERAP1 p.Thr12Ile (c.35C>T) in the general population?

ERAP1 p.Thr12Ile (c.35C>T) is common (popmax 13.1%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.35C>T · rs72773968 · VCV2688453

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0997 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 13.1%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0997	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -7.74	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 0.41	GERP -3.3
Regional constraint	o/e 0.86	unconstrained · MANE · 10 kb · p 0.003 · regional, not allelic
Overall
CADD	3.009	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 13.1% Admixed American · 7,886/60,006 alleles

Filtering AF 12.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.8%

Overall 11.7% 188,886/1,610,544 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	17.3%	6
Admixed Americangrpmax	13.1%	8
Ashkenazi Jewishnot grpmax-eligible	12.8%	8
European (non-Finnish)	12.8%	8
Finnishnot grpmax-eligible	12%	8
Middle Eastern	11.7%	9
Remaining individualsnot grpmax-eligible	11.6%	9
South Asian	10.1%	10
African / African-American	2.15%	47
East Asian	0.341%	293

Amish 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.Thr12Ile
Coding: c.35C>T
MANE Select: NM_001040458
dbSNP: rs72773968
Type: single nucleotide variant
Location: chr5:96803892 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.78 · 27 PDB

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-thr12ile (accessed [today's date]).

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