Is EP400 p.Ser45Pro (c.133T>C) pathogenic?

EP400 p.Ser45Pro (c.133T>C) is classified Uncertain significance in EP400 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-15). Very rare (popmax 0.000114%, nfe); Associated with EP400-related disorder.

What condition is associated with EP400 p.Ser45Pro (c.133T>C)?

EP400 p.Ser45Pro (c.133T>C) is associated with EP400-related disorder (ClinVar).

How common is EP400 p.Ser45Pro (c.133T>C) in the general population?

EP400 p.Ser45Pro (c.133T>C) is very rare (popmax 0.000114%, nfe) (gnomAD).

EP400 p.Ser45Pro

c.133T>C · rs1397691750 · VCV2631342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000114%, nfe)

Conditions

EP400-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.386	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 549 bp · p 5.4e-06 · regional, not allelic
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000114% European (non-Finnish) · 1/875,544 alleles

Overall 9.23e-05% 1/1,083,022 alleles · very rare exomes 0/1,012,264 · genomes 1/70,758 · joint denominator

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: EP400
Protein: p.Ser45Pro
Coding: c.133T>C
MANE Select: NM_015409
dbSNP: rs1397691750
Type: single nucleotide variant
Location: chr12:131960752 (GRCh38)
Gene constraint: LOEUF 0.365 · pLI 1.00 (gnomAD)
Residue 45: the 'disordered' region

Full EP400 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

EP400-related disorder

Similar variants

EP400 p.Gly2702Glu Uncertain significance ★ same condition
EP400 p.Lys1297Arg Uncertain significance ★ same condition
EP400 p.Ser573Phe Uncertain significance ★ same condition
EP400 c.2680-3C>A Uncertain significance same condition
EP400 c.4110+2T>A Uncertain significance same condition
EP400 c.5584+1G>A Uncertain significance same condition
EP400 p.Arg1295Ter Uncertain significance same condition
EP400 p.Asn2615Ser Uncertain significance 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/ep400-p-ser45pro (accessed [today's date]).

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