Is UBE3C p.Pro253= (c.759G>A) pathogenic?

UBE3C p.Pro253= (c.759G>A) is classified Benign in UBE3C (ClinVar, No assertion criteria, 2 submitters; last evaluated 2020-01-13). Common (popmax 7.47%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with UBE3C-related disorder.

What condition is associated with UBE3C p.Pro253= (c.759G>A)?

UBE3C p.Pro253= (c.759G>A) is associated with UBE3C-related disorder (ClinVar).

UBE3C p.Pro253=

Q: How common is UBE3C p.Pro253= (c.759G>A) in the general population?

UBE3C p.Pro253= (c.759G>A) is common (popmax 7.47%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.759G>A · rs17646047 · VCV3056835

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 7.47%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

UBE3C-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.49	GERP -3
Overall
CADD	5.993	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.47% European (non-Finnish) · 88,157/1,179,690 alleles

Filtering AF 7.43% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.41%

Overall 6.37% 102,745/1,613,138 alleles · common exomes 95,768/1,460,912 · genomes 6,977/152,226 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	7.47%	13
Remaining individualsnot grpmax-eligible	6.13%	16
Ashkenazi Jewishnot grpmax-eligible	5.66%	18
Finnishnot grpmax-eligible	4.45%	22
Admixed American	3.35%	30
South Asian	3.29%	30
Middle Eastern	3.12%	32
Amishnot grpmax-eligible	2.3%	43
African / African-American	1.16%	86
East Asian	0.359%	279

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: UBE3C
Protein: p.Pro253=
Coding: c.759G>A
MANE Select: NM_014671
dbSNP: rs17646047
Type: single nucleotide variant
Location: chr7:157181660 (GRCh38)
Gene constraint: LOEUF 0.427 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.82 · 1 PDB

Full UBE3C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

UBE3C-related disorder

Similar variants

UBE3C p.Asn744Asp Uncertain significance ⚠ same condition
UBE3C c.1143+9C>T Likely benign same condition
UBE3C c.459-8T>C Benign same condition
UBE3C p.Gln934Pro Likely benign same condition
UBE3C p.His755= Likely benign same condition
UBE3C p.Tyr501= Benign same condition
UBE3C p.Ala918= Likely benign ★★ same type
UBE3C c.2694+5G>C Uncertain significance ★ same type

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/ube3c-p-pro253 (accessed [today's date]).

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