Is UNG p.Pro176Leu (c.527C>T) pathogenic?

UNG p.Pro176Leu (c.527C>T) is classified Uncertain significance in UNG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-19). AlphaMissense: likely pathogenic (0.9262); Very rare (popmax 0.00432%, nfe); Associated with hyper-IgM syndrome type 5.

What condition is associated with UNG p.Pro176Leu (c.527C>T)?

UNG p.Pro176Leu (c.527C>T) is associated with hyper-IgM syndrome type 5 (ClinVar).

How common is UNG p.Pro176Leu (c.527C>T) in the general population?

UNG p.Pro176Leu (c.527C>T) is very rare (popmax 0.00432%, nfe) (gnomAD).

What do computational predictors say about UNG p.Pro176Leu (c.527C>T)?

AlphaMissense predicts likely pathogenic (score 0.9262) — an in-silico prediction, not a clinical call.

UNG p.Pro176Leu

c.527C>T · rs970951562 · VCV2164408

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9262 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00432%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyper-IgM syndrome type 5

Computational evidence

Protein change
AlphaMissense	0.9262	likely pathogenic
REVEL	0.769	pathogenic-leaning
SaProt	LLR -13.97	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 4.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 12 kb · p 0.74 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00432% European (non-Finnish) · 51/1,179,880 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00347% 56/1,613,714 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,819
European (non-Finnish)grpmax	0.00432%	23,135
African / African-American	0.00133%	74,920
South Asian	0.0011%	91,072

Remaining individuals 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: UNG
Protein: p.Pro176Leu
Coding: c.527C>T
MANE Select: NM_080911
dbSNP: rs970951562
Type: single nucleotide variant
Location: chr12:109101993 (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.Pro176= Benign ★★ 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-pro176leu (accessed [today's date]).

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