Is POLE p.Pro338= (c.1014C>T) pathogenic?

POLE p.Pro338= (c.1014C>T) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-11-18). Rare (popmax 0.118%, eas); Associated with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency.

How common is POLE p.Pro338= (c.1014C>T) in the general population?

POLE p.Pro338= (c.1014C>T) is rare (popmax 0.118%, eas) (gnomAD).

POLE p.Pro338=

Q: What condition is associated with POLE p.Pro338= (c.1014C>T)?

POLE p.Pro338= (c.1014C>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.1014C>T · rs143102561 · VCV383198

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.118%, eas)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.7	GERP -3.4
Overall
CADD	0.185	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.118% East Asian · 53/44,822 alleles

Filtering AF 0.0928% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0837%

Overall 0.00375% 60/1,598,174 alleles · rare exomes 53/1,445,894 · genomes 7/152,280 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.118%	846
European (non-Finnish)	0.000599%	167,008

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.Pro338=
Coding: c.1014C>T
MANE Select: NM_006231
dbSNP: rs143102561
Type: single nucleotide variant
Location: chr12:132676100 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB

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.Pro338Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro338Ala Uncertain significance ★ ⚠ same residue
POLE p.Pro338Ser Uncertain significance ★ ⚠ same residue
POLE p.Pro338Thr 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

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-pro338 (accessed [today's date]).

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