Is EPG5 p.Phe688Ser (c.2063T>C) pathogenic?

EPG5 p.Phe688Ser (c.2063T>C) is classified Conflicting classifications of pathogenicity in EPG5 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-21). AlphaMissense: likely pathogenic (0.8983); Rare (popmax 0.934%, afr); Associated with Inborn genetic diseases.

What condition is associated with EPG5 p.Phe688Ser (c.2063T>C)?

EPG5 p.Phe688Ser (c.2063T>C) is associated with Inborn genetic diseases, Vici syndrome (ClinVar).

How common is EPG5 p.Phe688Ser (c.2063T>C) in the general population?

EPG5 p.Phe688Ser (c.2063T>C) is rare (popmax 0.934%, afr) (gnomAD).

What do computational predictors say about EPG5 p.Phe688Ser (c.2063T>C)?

AlphaMissense predicts likely pathogenic (score 0.8983) — an in-silico prediction, not a clinical call.

EPG5 p.Phe688Ser

c.2063T>C · rs61978576 · VCV235421

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8983 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.934%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8983	likely pathogenic · top 8% in EPG5
REVEL	0.671	pathogenic-leaning
SaProt	LLR -8.85	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 52 kb · p 0.29 · regional, not allelic
Overall
CADD	26.9	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 0.934% African / African-American · 701/75,046 alleles

Filtering AF 0.877% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.854%

Overall 0.0482% 778/1,614,148 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.934%	107
Admixed American	0.065%	1,539
Remaining individualsnot grpmax-eligible	0.0368%	2,718
Middle Eastern	0.0165%	6,052
European (non-Finnish)	0.0011%	90,770
South Asian	0.0011%	91,078

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.Phe688Ser
Coding: c.2063T>C
MANE Select: NM_020964
dbSNP: rs61978576
Type: single nucleotide variant
Location: chr18:45939636 (GRCh38)
Gene constraint: LOEUF 0.58 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.24 · 1 PDB
Residue 688: a UniProt-annotated variant site (in vicis)

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 p.Phe688_Leu689insTer Pathogenic ★ 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-phe688ser (accessed [today's date]).

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