Is EPX p.Arg419Trp (c.1255C>T) pathogenic?

EPX p.Arg419Trp (c.1255C>T) is classified Uncertain significance in EPX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). AlphaMissense: likely pathogenic (0.7463); Ultra-rare (popmax 0.0165%, mid).

How common is EPX p.Arg419Trp (c.1255C>T) in the general population?

EPX p.Arg419Trp (c.1255C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about EPX p.Arg419Trp (c.1255C>T)?

AlphaMissense predicts likely pathogenic (score 0.7463) — an in-silico prediction, not a clinical call.

EPX p.Arg419Trp

c.1255C>T · rs139973119 · VCV2391972

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7463 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7463	likely pathogenic
REVEL	0.678	pathogenic-leaning
SaProt	LLR -14.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13	GERP -0.96, phastCons 0.002
Regional constraint	o/e 0.98	unconstrained · MANE · 12 kb · p 0.44 · regional, not allelic
Overall
CADD	22.7	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00118% 19/1,614,056 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0048%	20,835
East Asian	0.00223%	44,878
African / African-American	0.00133%	75,030
European (non-Finnish)	0.0011%	90,767

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.Arg419Trp
Coding: c.1255C>T
MANE Select: NM_000502
dbSNP: rs139973119
Type: single nucleotide variant
Location: chr17:58199174 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.40 · 1 PDB
Residue 419: an α-helix

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-arg419trp (accessed [today's date]).

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