Is EPX p.Arg364Cys (c.1090C>T) pathogenic?

EPX p.Arg364Cys (c.1090C>T) is classified Uncertain significance in EPX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.2066); Ultra-rare (popmax 0.0825%, mid).

How common is EPX p.Arg364Cys (c.1090C>T) in the general population?

EPX p.Arg364Cys (c.1090C>T) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

What do computational predictors say about EPX p.Arg364Cys (c.1090C>T)?

AlphaMissense predicts likely benign (score 0.2066) — an in-silico prediction, not a clinical call.

EPX p.Arg364Cys

c.1090C>T · rs573827983 · VCV2271284

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2066 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2066	likely benign
REVEL	0.51	indeterminate
SaProt	LLR -12.70	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 2.3, phastCons 0.97
Regional constraint	o/e 0.98	unconstrained · MANE · 12 kb · p 0.44 · regional, not allelic
Overall
CADD	25.9	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 0.0825% Middle Eastern · 5/6,060 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00198% 32/1,612,868 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0825%	1,212
African / African-American	0.00933%	10,721
Finnishnot grpmax-eligible	0.00797%	12,543
South Asian	0.00439%	22,770
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Admixed American	0.00167%	60,028
Remaining individualsnot grpmax-eligible	0.0016%	62,498
European (non-Finnish)	0.000678%	147,504

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: EPX
Protein: p.Arg364Cys
Coding: c.1090C>T
MANE Select: NM_000502
dbSNP: rs573827983
Type: single nucleotide variant
Location: chr17:58197227 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.40 · 1 PDB
Residue 364: a disulfide bond; a UniProt-annotated variant site (in); a turn

Full EPX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPX c.170+5A>G Likely benign ★★ same type
EPX c.464+8C>T Benign ★★ same type
EPX c.801+1G>A Likely benign ★★ same type
EPX p.Asn572Tyr Benign ★★ same type
EPX p.Cys257Ter Benign ★★ same type
EPX p.Leu624= Benign/Likely benign ★★ same type
EPX p.Phe308Leu Likely benign ★★ ⚠ same type
EPX p.Pro292Leu Benign ★★ 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/epx-p-arg364cys (accessed [today's date]).

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