Is POLE c.720+1G>A pathogenic?

POLE c.720+1G>A is classified Likely pathogenic in POLE (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-15). Absent from gnomAD v4.1; Associated with facial dysmorphism-immunodeficiency-livedo-short stature syndrome.

How common is POLE c.720+1G>A in the general population?

POLE c.720+1G>A is absent from gnomAD v4.1 (gnomAD).

POLE c.720+1G>A

Q: What condition is associated with POLE c.720+1G>A?

POLE c.720+1G>A is associated with facial dysmorphism-immunodeficiency-livedo-short stature syndrome, familial colorectal cancer (ClinVar).

Q: How is Facial dysmorphism-immunodeficiency-livedo-short stature syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

rs1060500808 · VCV405681

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

facial dysmorphism-immunodeficiency-livedo-short stature syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +1	canonical splice dinucleotide (donor +1) · inside the BP7-excluded zone
SpliceAI	Δ1.00	donor loss, 1 bp away · masked 0 · deltas
Pangolin	Δ0.91	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Non-coding constraint	Z 1.92	1 kb window · o/e 0.88 · regional · uncalibrated
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: POLE
Coding: c.720+1G>A
MANE Select: NM_006231
dbSNP: rs1060500808
Type: single nucleotide variant
Location: chr12:132677577 (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

facial dysmorphism-immunodeficiency-livedo-short stature syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial colorectal cancer

For Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

POLE p.Leu424Val Pathogenic ★★ same condition
POLE c.5378+4C>T Uncertain significance ★★ same condition
POLE c.6747+5G>A Uncertain significance ★★ same condition
POLE p.Ala1149Val Uncertain significance ★★ ⚠ same condition
POLE p.Ala1323Val Uncertain significance ★★ ⚠ same condition
POLE p.Ala1349Val Uncertain significance ★★ ⚠ same condition
POLE p.Ala1493Thr Uncertain significance ★★ ⚠ same condition
POLE p.Ala1597Thr 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-c-720-plus-1g-a (accessed [today's date]).

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