Is POLE p.Lys795Arg (c.2384A>G) pathogenic?

POLE p.Lys795Arg (c.2384A>G) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.0663); Rare (popmax 0.165%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Lys795Arg (c.2384A>G)?

POLE p.Lys795Arg (c.2384A>G) is associated with hereditary neoplastic syndrome, colorectal cancer, susceptibility to, 12, facial dysmorphism-immunodeficiency-livedo-short stature syndrome (ClinVar).

How common is POLE p.Lys795Arg (c.2384A>G) in the general population?

POLE p.Lys795Arg (c.2384A>G) is rare (popmax 0.165%, mid) (gnomAD).

What do computational predictors say about POLE p.Lys795Arg (c.2384A>G)?

AlphaMissense predicts likely benign (score 0.0663) — an in-silico prediction, not a clinical call.

POLE p.Lys795Arg

c.2384A>G · rs867677414 · VCV540644

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0663 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0663	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -6.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -3.7
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	13.18	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.165% Middle Eastern · 10/6,062 alleles

Filtering AF 0.0895% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0681%

Overall 0.00105% 17/1,613,904 alleles · rare exomes 17/1,461,622 · genomes 0/152,282 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.165%	606
Remaining individualsnot grpmax-eligible	0.0048%	20,834
Admixed American	0.00167%	60,022
African / African-American	0.00133%	75,030
European (non-Finnish)	0.000169%	590,009

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.Lys795Arg
Coding: c.2384A>G
MANE Select: NM_006231
dbSNP: rs867677414
Type: single nucleotide variant
Location: chr12:132665386 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 795: an α-helix; a UniProt-annotated variant site (in imagei)

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

Disease context

hereditary neoplastic syndrome — 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 intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Similar variants

POLE p.Lys795= Conflicting classifications of pathogenicity ★ same residue
POLE p.Lys795Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Lys795Glu 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

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-lys795arg (accessed [today's date]).

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