Is EPG5 p.Pro1306Ser (c.3916C>T) pathogenic?

EPG5 p.Pro1306Ser (c.3916C>T) is classified Uncertain significance in EPG5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-01). AlphaMissense: ambiguous (0.4975); Very rare (popmax 0.00337%, amr); Associated with Vici syndrome.

What condition is associated with EPG5 p.Pro1306Ser (c.3916C>T)?

EPG5 p.Pro1306Ser (c.3916C>T) is associated with Vici syndrome (ClinVar).

How common is EPG5 p.Pro1306Ser (c.3916C>T) in the general population?

EPG5 p.Pro1306Ser (c.3916C>T) is very rare (popmax 0.00337%, amr) (gnomAD).

What do computational predictors say about EPG5 p.Pro1306Ser (c.3916C>T)?

AlphaMissense predicts ambiguous (score 0.4975) — an in-silico prediction, not a clinical call.

EPG5 p.Pro1306Ser

c.3916C>T · VCV4018599

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4975 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00337%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Vici syndrome

Computational evidence

Protein change
AlphaMissense	0.4975	ambiguous
REVEL	0.782	moderately pathogenic-leaning
SaProt	LLR -5.73	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 33 kb · p 0.78 · regional, not allelic
Overall
CADD	27.5	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 0.00337% Admixed American · 2/59,322 alleles

Filtering AF 0.000559% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000209%

Overall 0.000137% 2/1,459,362 alleles · very rare

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.Pro1306Ser
Coding: c.3916C>T
MANE Select: NM_020964
Type: single nucleotide variant
Location: chr18:45912357 (GRCh38)
Gene constraint: LOEUF 0.58 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.24 · 1 PDB
Residue 1306: 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.Pro1306= Likely benign ★ same residue
EPG5 p.Pro1306Leu 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

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-pro1306ser (accessed [today's date]).

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