Is EPX p.Arg340His (c.1019G>A) pathogenic?

EPX p.Arg340His (c.1019G>A) is classified Uncertain significance in EPX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-05). AlphaMissense: likely benign (0.0683); Very rare (popmax 0.01%, amr).

How common is EPX p.Arg340His (c.1019G>A) in the general population?

EPX p.Arg340His (c.1019G>A) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about EPX p.Arg340His (c.1019G>A)?

AlphaMissense predicts likely benign (score 0.0683) — an in-silico prediction, not a clinical call.

EPX p.Arg340His

c.1019G>A · VCV3845689

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0683 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0683	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -8.25	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 -8.8	GERP -4.7
Regional constraint	o/e 0.98	unconstrained · MANE · 12 kb · p 0.44 · regional, not allelic
Overall
CADD	1.818	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.01% Admixed American · 6/60,012 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00446% 72/1,614,044 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0641%	1,561
Admixed Americangrpmax	0.01%	10,002
Remaining individualsnot grpmax-eligible	0.0096%	10,415
South Asian	0.00659%	15,181
African / African-American	0.00133%	74,930
European (non-Finnish)	0.00102%	98,337

Finnish 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: EPX
Protein: p.Arg340His
Coding: c.1019G>A
MANE Select: NM_000502
Type: single nucleotide variant
Location: chr17:58197156 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.40 · 1 PDB

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-arg340his (accessed [today's date]).

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