Is U2AF2 p.Pro418= (c.1254C>T) pathogenic?

U2AF2 p.Pro418= (c.1254C>T) is classified Benign in U2AF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-01). Low-frequency (popmax 2.4%, mid).

How common is U2AF2 p.Pro418= (c.1254C>T) in the general population?

U2AF2 p.Pro418= (c.1254C>T) is low-frequency (popmax 2.4%, mid) (gnomAD).

U2AF2 p.Pro418=

c.1254C>T · rs147666260 · VCV2650537

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 2.4%, mid)

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 -0.3	GERP -0.65, phastCons 0.12
Overall
CADD	7.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.4% Middle Eastern · 125/5,214 alleles

Filtering AF 2.06% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.93%

Overall 0.747% 12,040/1,612,418 alleles · low-frequency exomes 11,109/1,460,158 · genomes 931/152,260 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	3.77%	27
Middle Easterngrpmax	2.4%	42
Remaining individualsnot grpmax-eligible	0.989%	101
European (non-Finnish)	0.769%	130
Admixed American	0.617%	162
South Asian	0.427%	234
Finnishnot grpmax-eligible	0.361%	277
African / African-American	0.169%	590
East Asian	0.00446%	22,437

Ashkenazi Jewish 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: U2AF2
Protein: p.Pro418=
Coding: c.1254C>T
MANE Select: NM_007279
dbSNP: rs147666260
Type: single nucleotide variant
Location: chr19:55669653 (GRCh38)
Gene constraint: LOEUF 0.209 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.24 · 40 PDB
Residue 418: the rrm 3 domain

Full U2AF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

U2AF2 p.Arg149Gln Pathogenic/Likely pathogenic ★★ same type
U2AF2 p.Arg149Trp Pathogenic ★★ same type
U2AF2 p.Arg150Cys Pathogenic/Likely pathogenic ★★ same type
U2AF2 p.Arg150His Pathogenic/Likely pathogenic ★★ same type
U2AF2 p.Val153Met Pathogenic ★★ same type
U2AF2 p.His470Gln Uncertain significance ★★ ⚠ same type
U2AF2 p.Asp391= Likely benign ★★ same type
U2AF2 p.Ser243= Likely benign ★★ 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/u2af2-p-pro418 (accessed [today's date]).

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