Is EPG5 p.Phe2015Ser (c.6044T>C) pathogenic?

EPG5 p.Phe2015Ser (c.6044T>C) is classified Uncertain significance in EPG5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-20). AlphaMissense: ambiguous (0.5485); Ultra-rare (popmax 0.0383%, amr); Associated with Inborn genetic diseases.

What condition is associated with EPG5 p.Phe2015Ser (c.6044T>C)?

EPG5 p.Phe2015Ser (c.6044T>C) is associated with Inborn genetic diseases, Vici syndrome (ClinVar).

How common is EPG5 p.Phe2015Ser (c.6044T>C) in the general population?

EPG5 p.Phe2015Ser (c.6044T>C) is ultra-rare (popmax 0.0383%, amr) (gnomAD).

What do computational predictors say about EPG5 p.Phe2015Ser (c.6044T>C)?

AlphaMissense predicts ambiguous (score 0.5485) — an in-silico prediction, not a clinical call.

EPG5 p.Phe2015Ser

c.6044T>C · rs756154171 · VCV649018

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5485 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0383%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5485	ambiguous
REVEL	0.306	indeterminate
SaProt	LLR -9.76	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 24 kb · p 0.0015 · regional, not allelic
Overall
CADD	24.0	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 0.0383% Admixed American · 23/59,992 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00149% 24/1,610,256 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0383%	2,608
European (non-Finnish)	8.5e-05%	1,176,598

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: EPG5
Protein: p.Phe2015Ser
Coding: c.6044T>C
MANE Select: NM_020964
dbSNP: rs756154171
Type: single nucleotide variant
Location: chr18:45876241 (GRCh38)
Gene constraint: LOEUF 0.58 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.24 · 1 PDB
Residue 2015: a UniProt-annotated variant site (in vicis); a UniProt-annotated variant site (in nedpam)

Full EPG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Vici syndrome

Similar variants

EPG5 c.1253-1G>A Pathogenic ★★ same condition
EPG5 c.1497+1G>T Pathogenic/Likely pathogenic ★★ same condition
EPG5 c.1678-1G>A Likely pathogenic ★★ same condition
EPG5 c.4475-1G>A Likely pathogenic ★★ same condition
EPG5 c.5304+1G>A Likely pathogenic ★★ same condition
EPG5 c.5869+1G>A Pathogenic ★★ same condition
EPG5 c.6049+5G>A Likely pathogenic ★★ same condition
EPG5 p.Arg1161Ter Pathogenic ★★ same condition

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/epg5-p-phe2015ser (accessed [today's date]).

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