Is EPX p.Arg124Trp (c.370C>T) pathogenic?

EPX p.Arg124Trp (c.370C>T) is classified Uncertain significance in EPX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely benign (0.0768); Ultra-rare (popmax 0.0424%, mid).

How common is EPX p.Arg124Trp (c.370C>T) in the general population?

EPX p.Arg124Trp (c.370C>T) is ultra-rare (popmax 0.0424%, mid) (gnomAD).

What do computational predictors say about EPX p.Arg124Trp (c.370C>T)?

AlphaMissense predicts likely benign (score 0.0768) — an in-silico prediction, not a clinical call.

EPX p.Arg124Trp

c.370C>T · rs759899408 · VCV3090007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0768 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0424%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0768	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -10.72	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.2	GERP -4
Regional constraint	o/e 0.98	unconstrained · MANE · 12 kb · p 0.44 · regional, not allelic
Overall
CADD	12.55	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 0.0424% Middle Eastern · 2/4,716 alleles

Filtering AF 0.00758% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00706%

Overall 0.00763% 123/1,611,896 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0424%	2,358
Remaining individualsnot grpmax-eligible	0.0128%	7,794
European (non-Finnish)	0.00899%	11,127
Admixed American	0.005%	20,001
Finnishnot grpmax-eligible	0.00312%	32,008
South Asian	0.0022%	45,476

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.Arg124Trp
Coding: c.370C>T
MANE Select: NM_000502
dbSNP: rs759899408
Type: single nucleotide variant
Location: chr17:58193737 (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-arg124trp (accessed [today's date]).

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