Is EPG5 p.Pro1663Leu (c.4988C>T) pathogenic?

EPG5 p.Pro1663Leu (c.4988C>T) is classified Uncertain significance in EPG5 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-12-09). AlphaMissense: likely benign (0.0751); Very rare (popmax 0.0073%, nfe); Associated with Vici syndrome.

What condition is associated with EPG5 p.Pro1663Leu (c.4988C>T)?

EPG5 p.Pro1663Leu (c.4988C>T) is associated with Vici syndrome (ClinVar).

How common is EPG5 p.Pro1663Leu (c.4988C>T) in the general population?

EPG5 p.Pro1663Leu (c.4988C>T) is very rare (popmax 0.0073%, nfe) (gnomAD).

What do computational predictors say about EPG5 p.Pro1663Leu (c.4988C>T)?

AlphaMissense predicts likely benign (score 0.0751) — an in-silico prediction, not a clinical call.

EPG5 p.Pro1663Leu

c.4988C>T · rs375606930 · VCV659220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0751 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0073%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Vici syndrome

Computational evidence

Protein change
AlphaMissense	0.0751	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -8.29	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 6.7	GERP -1.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 33 kb · p 0.78 · regional, not allelic
Overall
CADD	19.98	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 0.0073% European (non-Finnish) · 85/1,164,488 alleles

Filtering AF 0.00604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00556%

Overall 0.0054% 86/1,593,048 alleles · very rare exomes 85/1,440,880 · genomes 1/152,168 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0073%	13,700
Remaining individualsnot grpmax-eligible	0.00163%	61,218

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.Pro1663Leu
Coding: c.4988C>T
MANE Select: NM_020964
dbSNP: rs375606930
Type: single nucleotide variant
Location: chr18:45887872 (GRCh38)
Gene constraint: LOEUF 0.58 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.24 · 1 PDB
Residue 1663: 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.Pro1663= Likely benign ★★ 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-pro1663leu (accessed [today's date]).

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