Is POLE p.Tyr84= (c.252C>T) pathogenic?

POLE p.Tyr84= (c.252C>T) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.0338%, nfe); Associated with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency.

How common is POLE p.Tyr84= (c.252C>T) in the general population?

POLE p.Tyr84= (c.252C>T) is ultra-rare (popmax 0.0338%, nfe) (gnomAD).

POLE p.Tyr84=

Q: What condition is associated with POLE p.Tyr84= (c.252C>T)?

POLE p.Tyr84= (c.252C>T) is associated with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency, colorectal cancer, susceptibility to, 12, facial dysmorphism-immunodeficiency-livedo-short stature syndrome (ClinVar).

c.252C>T · rs148838481 · VCV413542

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0338%, nfe)

Conditions

intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1.5, phastCons 1
Overall
CADD	10.71	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0338% European (non-Finnish) · 399/1,179,944 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.0251% 405/1,613,944 alleles · ultra-rare exomes 385/1,461,750 · genomes 20/152,194 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0338%	2,957
African / African-American	0.00534%	18,726
Remaining individualsnot grpmax-eligible	0.0032%	31,239

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: POLE
Protein: p.Tyr84=
Coding: c.252C>T
MANE Select: NM_006231
dbSNP: rs148838481
Type: single nucleotide variant
Location: chr12:132680640 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 84: a β-strand

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

Disease context

intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer, susceptibility to, 12 facial dysmorphism-immunodeficiency-livedo-short stature syndrome hereditary neoplastic syndrome

Similar variants

POLE p.Tyr84Cys Uncertain significance ★★ ⚠ same residue
POLE p.Tyr84His Uncertain significance ★★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T Pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ same condition
POLE c.1020+5G>A Uncertain significance ★★ same condition
POLE c.1106+3G>C Uncertain significance ★★ same condition
POLE c.1106+4A>G 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/pole-p-tyr84 (accessed [today's date]).

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