Is ERAP2 p.Ser234Phe (c.701C>T) pathogenic?

ERAP2 p.Ser234Phe (c.701C>T) is classified Uncertain significance in ERAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely pathogenic (0.5761); Ultra-rare (popmax 0.0953%, sas).

How common is ERAP2 p.Ser234Phe (c.701C>T) in the general population?

ERAP2 p.Ser234Phe (c.701C>T) is ultra-rare (popmax 0.0953%, sas) (gnomAD).

What do computational predictors say about ERAP2 p.Ser234Phe (c.701C>T)?

AlphaMissense predicts likely pathogenic (score 0.5761) — an in-silico prediction, not a clinical call.

ERAP2 p.Ser234Phe

c.701C>T · VCV4665040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5761 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0953%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5761	likely pathogenic
REVEL	0.484	indeterminate
SaProt	LLR -11.91	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 1.9	GERP 1.4, phastCons 0.8
Regional constraint	o/e 0.99	unconstrained · MANE · 30 kb · p 0.75 · regional, not allelic
Overall
CADD	24.0	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 0.0953% South Asian · 85/89,192 alleles

Filtering AF 0.0789% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0728%

Overall 0.00542% 87/1,605,976 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0953%	1,049
Middle Eastern	0.0166%	6,040
Remaining individualsnot grpmax-eligible	0.00161%	62,206

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.Ser234Phe
Coding: c.701C>T
MANE Select: NM_001040458 · reported on NM_022350
Type: single nucleotide variant
Location: chr5:96883917 (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-ser234phe (accessed [today's date]).

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