Is UNG p.Leu253= (c.759C>G) pathogenic?

UNG p.Leu253= (c.759C>G) is classified Benign in UNG (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). Common (popmax 6.61%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hyper-IgM syndrome type 5.

What condition is associated with UNG p.Leu253= (c.759C>G)?

UNG p.Leu253= (c.759C>G) is associated with hyper-IgM syndrome type 5 (ClinVar).

UNG p.Leu253=

Q: How common is UNG p.Leu253= (c.759C>G) in the general population?

UNG p.Leu253= (c.759C>G) is common (popmax 6.61%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.759C>G · rs76391872 · VCV306977

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 6.61%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

hyper-IgM syndrome type 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.287	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.22	GERP 1.4, phastCons 0.97
Overall
CADD	7.877	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.61% African / African-American · 4,955/74,968 alleles

Filtering AF 6.46% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.39%

Overall 0.341% 5,504/1,613,926 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.61%	15
Remaining individualsnot grpmax-eligible	0.366%	273
Admixed American	0.362%	277
Middle Eastern	0.336%	298
South Asian	0.00988%	10,117
European (non-Finnish)	0.00627%	15,946

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: UNG
Protein: p.Leu253=
Coding: c.759C>G
MANE Select: NM_080911
dbSNP: rs76391872
Type: single nucleotide variant
Location: chr12:109103569 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.52 · 24 PDB
Residue 253: a β-strand

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

Disease context

hyper-IgM syndrome type 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

UNG c.623-9T>A Uncertain significance ★★ same condition
UNG c.801+5G>A Uncertain significance ★★ same condition
UNG p.Ala21Thr Uncertain significance ★★ ⚠ same condition
UNG p.Ala87Val Uncertain significance ★★ ⚠ same condition
UNG p.Arg122Ser Uncertain significance ★★ ⚠ same condition
UNG p.Arg269Trp Uncertain significance ★★ ⚠ same condition
UNG p.Asn77Lys Uncertain significance ★★ ⚠ same condition
UNG p.Gln133His 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/ung-p-leu253 (accessed [today's date]).

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