Is POLE p.Phe1708= (c.5124C>T) pathogenic?

POLE p.Phe1708= (c.5124C>T) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-02). Rare (popmax 0.547%, afr); Associated with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency.

How common is POLE p.Phe1708= (c.5124C>T) in the general population?

POLE p.Phe1708= (c.5124C>T) is rare (popmax 0.547%, afr) (gnomAD).

POLE p.Phe1708=

Q: What condition is associated with POLE p.Phe1708= (c.5124C>T)?

POLE p.Phe1708= (c.5124C>T) is associated with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency, colon carcinoma, colorectal cancer, susceptibility to, 12 (ClinVar).

c.5124C>T · rs114891564 · VCV240550

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

rare (popmax 0.547%, afr)

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 -4.6
Overall
CADD	0.19	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.547% African / African-American · 410/74,916 alleles

Filtering AF 0.504% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.486%

Overall 0.0273% 440/1,608,942 alleles · rare exomes 231/1,456,650 · genomes 209/152,292 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.547%	183
Remaining individualsnot grpmax-eligible	0.0177%	5,658
Admixed American	0.0168%	5,939
South Asian	0.00333%	30,052
European (non-Finnish)	0.00051%	196,240

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.Phe1708=
Coding: c.5124C>T
MANE Select: NM_006231
dbSNP: rs114891564
Type: single nucleotide variant
Location: chr12:132642226 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1708: a UniProt-annotated variant site (in imagei)

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

Similar variants

POLE p.Phe1708Leu 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
POLE c.1226+3A>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-phe1708 (accessed [today's date]).

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