Is UBA2 p.Arg274Trp (c.820C>T) pathogenic?

UBA2 p.Arg274Trp (c.820C>T) is classified Uncertain significance in UBA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-20). AlphaMissense: ambiguous (0.4543); Ultra-rare (popmax 0.0119%, amr); Associated with Inborn genetic diseases.

What condition is associated with UBA2 p.Arg274Trp (c.820C>T)?

UBA2 p.Arg274Trp (c.820C>T) is associated with Inborn genetic diseases, ACCES syndrome (ClinVar).

How common is UBA2 p.Arg274Trp (c.820C>T) in the general population?

UBA2 p.Arg274Trp (c.820C>T) is ultra-rare (popmax 0.0119%, amr) (gnomAD).

What do computational predictors say about UBA2 p.Arg274Trp (c.820C>T)?

AlphaMissense predicts ambiguous (score 0.4543) — an in-silico prediction, not a clinical call.

UBA2 p.Arg274Trp

c.820C>T · rs531406361 · VCV2521911

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4543 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4543	ambiguous
REVEL	0.174	moderately benign-leaning
SaProt	LLR -13.68	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.37	GERP -1.4, phastCons 0.99
Regional constraint	o/e 0.66	unconstrained · MANE · 25 kb · p 4.5e-13 · regional, not allelic
Overall
CADD	23.8	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 0.0119% Admixed American · 7/58,840 alleles

Filtering AF 0.00553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00386%

Overall 0.00329% 53/1,610,330 alleles · ultra-rare exomes 43/1,458,190 · genomes 10/152,140 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0119%	8,406
Remaining individualsnot grpmax-eligible	0.00802%	12,468
South Asian	0.00443%	22,572
African / African-American	0.00402%	24,895
Finnishnot grpmax-eligible	0.00313%	31,924
European (non-Finnish)	0.00271%	36,846

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: UBA2
Protein: p.Arg274Trp
Coding: c.820C>T
MANE Select: NM_005499
dbSNP: rs531406361
Type: single nucleotide variant
Location: chr19:34450313 (GRCh38)
Gene constraint: LOEUF 0.258 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.72 · 16 PDB
Residue 274: a UniProt-annotated variant site (in acces); an α-helix

Full UBA2 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: ACCES syndrome

Similar variants

UBA2 p.Arg107Ter Likely pathogenic ★★ same condition
UBA2 p.Arg122Ter Pathogenic ★★ same condition
UBA2 p.Met1Val Pathogenic/Likely pathogenic ★★ same condition
UBA2 p.Ile468Leu Uncertain significance ★★ ⚠ same condition
UBA2 c.1038+1G>A Likely pathogenic ★ same condition
UBA2 c.460-2A>G Pathogenic ★ same condition
UBA2 c.582-1G>C Likely pathogenic ★ same condition
UBA2 c.649+1G>A 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/uba2-p-arg274trp (accessed [today's date]).

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