Is EPG5 p.Pro2174= (c.6522G>A) pathogenic?

EPG5 p.Pro2174= (c.6522G>A) is classified Benign/Likely benign in EPG5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-01). Low-frequency (popmax 1.22%, nfe); Associated with Vici syndrome.

What condition is associated with EPG5 p.Pro2174= (c.6522G>A)?

EPG5 p.Pro2174= (c.6522G>A) is associated with Vici syndrome (ClinVar).

How common is EPG5 p.Pro2174= (c.6522G>A) in the general population?

EPG5 p.Pro2174= (c.6522G>A) is low-frequency (popmax 1.22%, nfe) (gnomAD).

EPG5 p.Pro2174=

c.6522G>A · rs148683476 · VCV534619

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.22%, nfe)

Conditions

Vici syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3.5
Overall
CADD	0.061	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.22% European (non-Finnish) · 14,404/1,179,880 alleles

Filtering AF 1.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.2%

Overall 1.03% 16,593/1,613,994 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.22%	82
Remaining individualsnot grpmax-eligible	1.15%	87
South Asian	0.682%	147
Ashkenazi Jewishnot grpmax-eligible	0.554%	181
Finnishnot grpmax-eligible	0.487%	205
Admixed American	0.365%	274
African / African-American	0.188%	532
Middle Eastern	0.148%	674
East Asian	0.00891%	11,222

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.Pro2174=
Coding: c.6522G>A
MANE Select: NM_020964
dbSNP: rs148683476
Type: single nucleotide variant
Location: chr18:45866897 (GRCh38)
Gene constraint: LOEUF 0.58 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.24 · 1 PDB
Residue 2174: 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

Vici syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPG5 p.Pro2174Leu Uncertain significance ★★ ⚠ same residue
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

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-pro2174 (accessed [today's date]).

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