Is UBE3A p.Pro424= (c.1272C>T) pathogenic?

UBE3A p.Pro424= (c.1272C>T) is classified Likely benign in UBE3A (ClinVar, Expert panel, 4 submitters; last evaluated 2023-06-16). Very rare (popmax 0.000593%, nfe); Associated with Angelman syndrome.

What condition is associated with UBE3A p.Pro424= (c.1272C>T)?

UBE3A p.Pro424= (c.1272C>T) is associated with Angelman syndrome (ClinVar).

How common is UBE3A p.Pro424= (c.1272C>T) in the general population?

UBE3A p.Pro424= (c.1272C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

UBE3A p.Pro424=

c.1272C>T · rs1057520392 · VCV378843

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

Angelman syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Likely Benign for Angelman syndrome. Applied ACMG criteria (verbatim):

BP7 BP4

Curation rationale (ClinGen, verbatim)

The c.1212C>T p.Pro404= variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.0062% in the European (non-Finnish) sub population (no criteria met). The silent p.Pro404= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.1212C>T p.Pro404= variant in UBE3A is classified as Likely Benign based on the ACMG/AMP criteria (BP4, BP7).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -2	GERP -2.2
Overall
CADD	4.358	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,968 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,613,944 alleles · very rare exomes 8/1,461,798 · genomes 0/152,146 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)grpmax	0.000593%	168,567

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: UBE3A
Protein: p.Pro424=
Coding: c.1272C>T
MANE Select: NM_130839
dbSNP: rs1057520392
Type: single nucleotide variant
Location: chr15:25370902 (GRCh38)

Full UBE3A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Angelman syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/ube3a-p-pro424 (accessed [today's date]).

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