Is UNG p.Pro176= (c.528G>A) pathogenic?

UNG p.Pro176= (c.528G>A) is classified Benign in UNG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-20). Low-frequency (popmax 1.27%, sas); Associated with hyper-IgM syndrome type 5.

What condition is associated with UNG p.Pro176= (c.528G>A)?

UNG p.Pro176= (c.528G>A) is associated with hyper-IgM syndrome type 5 (ClinVar).

How common is UNG p.Pro176= (c.528G>A) in the general population?

UNG p.Pro176= (c.528G>A) is low-frequency (popmax 1.27%, sas) (gnomAD).

UNG p.Pro176=

c.528G>A · rs373915335 · VCV306972

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.27%, sas)

Conditions

hyper-IgM syndrome type 5

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 -8.7	GERP -9.7
Overall
CADD	1.266	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.27% South Asian · 1,157/91,060 alleles

Filtering AF 1.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.19%

Overall 0.0873% 1,409/1,613,808 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.27%	79
Middle Eastern	0.252%	396
Remaining individualsnot grpmax-eligible	0.0944%	1,059
Admixed American	0.015%	6,669
European (non-Finnish)	0.0141%	7,108
African / African-American	0.00267%	37,506
Finnishnot grpmax-eligible	0.00156%	64,016

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.Pro176=
Coding: c.528G>A
MANE Select: NM_080911
dbSNP: rs373915335
Type: single nucleotide variant
Location: chr12:109101994 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.52 · 24 PDB
Residue 176: an α-helix

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 p.Pro176Leu Uncertain significance ★★ ⚠ same residue
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

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-pro176 (accessed [today's date]).

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