Is ERAP2 p.Ser94Phe (c.281C>T) pathogenic?

ERAP2 p.Ser94Phe (c.281C>T) is classified Uncertain significance in ERAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: likely benign (0.1498); Very rare (popmax 0.00834%, amr).

How common is ERAP2 p.Ser94Phe (c.281C>T) in the general population?

ERAP2 p.Ser94Phe (c.281C>T) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about ERAP2 p.Ser94Phe (c.281C>T)?

AlphaMissense predicts likely benign (score 0.1498) — an in-silico prediction, not a clinical call.

ERAP2 p.Ser94Phe

c.281C>T · VCV3509748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1498 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1498	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -10.02	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.9	GERP 2.5, phastCons 0.39
Regional constraint	o/e 0.99	unconstrained · MANE · 30 kb · p 0.75 · regional, not allelic
Overall
CADD	20.9	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 0.00834% Admixed American · 5/59,988 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000558% 9/1,614,048 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,998
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000254%	393,346

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.Ser94Phe
Coding: c.281C>T
MANE Select: NM_001040458 · reported on NM_022350
Type: single nucleotide variant
Location: chr5:96879966 (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-ser94phe (accessed [today's date]).

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