Is UBE3A p.Phe446= (c.1338T>C) pathogenic?

UBE3A p.Phe446= (c.1338T>C) is classified Benign in UBE3A (ClinVar, Expert panel, 7 submitters; last evaluated 2022-12-08). Ultra-rare (popmax 0.0186%, nfe); Associated with Angelman syndrome.

What condition is associated with UBE3A p.Phe446= (c.1338T>C)?

UBE3A p.Phe446= (c.1338T>C) is associated with Angelman syndrome (ClinVar).

How common is UBE3A p.Phe446= (c.1338T>C) in the general population?

UBE3A p.Phe446= (c.1338T>C) is ultra-rare (popmax 0.0186%, nfe) (gnomAD).

UBE3A p.Phe446=

c.1338T>C · rs371154816 · VCV196572

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0186%, nfe)

Conditions

Angelman syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

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

BS1 BP7

Curation rationale (ClinGen, verbatim)

The allele frequency of the p.Phe426= variant in UBE3A (NM_130838.2) is 0.014% in European (non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Phe426= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Phe426= variant in UBE3A (NM_130838.2) is classified as Likely Benign based on the ACMG/AMP criteria (BS1, 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 assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -1.1, phastCons 1
Overall
CADD	7.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0186% European (non-Finnish) · 220/1,179,990 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0158%

Overall 0.0142% 230/1,614,140 alleles · ultra-rare exomes 216/1,461,804 · genomes 14/152,336 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0186%	5,364
Remaining individualsnot grpmax-eligible	0.0096%	10,418
Admixed American	0.00333%	30,009
African / African-American	0.00133%	75,062
South Asian	0.0011%	91,080

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.Phe446=
Coding: c.1338T>C
MANE Select: NM_130839
dbSNP: rs371154816
Type: single nucleotide variant
Location: chr15:25370836 (GRCh38)
Gene constraint: LOEUF 0.139 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.42 · 25 PDB
Residue 446: the 'interaction with hcv core protein' region; an α-helix

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

Similar variants

UBE3A c.2125-1G>A Likely pathogenic ★★★ same condition
UBE3A p.Arg526Cys Pathogenic ★★★ same condition
UBE3A p.Gly870Asp Likely pathogenic ★★★ same condition
UBE3A c.1609-8A>G Uncertain significance ★★★ same condition
UBE3A p.Asn581Ser Uncertain significance ★★★ ⚠ same condition
UBE3A p.Cys137Arg Uncertain significance ★★★ ⚠ same condition
UBE3A p.Phe805= Uncertain significance ★★★ same condition
UBE3A p.Thr807Ala 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/ube3a-p-phe446 (accessed [today's date]).

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