Is EPX p.Phe112Leu (c.334T>C) pathogenic?

EPX p.Phe112Leu (c.334T>C) is classified Uncertain significance in EPX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely pathogenic (0.6365); Very rare (popmax 0.00525%, nfe).

How common is EPX p.Phe112Leu (c.334T>C) in the general population?

EPX p.Phe112Leu (c.334T>C) is very rare (popmax 0.00525%, nfe) (gnomAD).

What do computational predictors say about EPX p.Phe112Leu (c.334T>C)?

AlphaMissense predicts likely pathogenic (score 0.6365) — an in-silico prediction, not a clinical call.

EPX p.Phe112Leu

c.334T>C · VCV4019082

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6365 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00525%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6365	likely pathogenic
REVEL	0.083	moderately benign-leaning
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.83	GERP 0.98, phastCons 0.97
Regional constraint	o/e 0.98	unconstrained · MANE · 12 kb · p 0.44 · regional, not allelic
Overall
CADD	17.43	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 0.00525% European (non-Finnish) · 62/1,179,998 alleles

Filtering AF 0.00418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00397% 64/1,613,992 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00525%	19,032
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,920

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.Phe112Leu
Coding: c.334T>C
MANE Select: NM_000502
Type: single nucleotide variant
Location: chr17:58193534 (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-phe112leu (accessed [today's date]).

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