Is POLE p.Arg1382His (c.4145G>A) pathogenic?

POLE p.Arg1382His (c.4145G>A) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1021); Ultra-rare (popmax 0.0401%, amr); Associated with facial dysmorphism-immunodeficiency-livedo-short stature syndrome.

What condition is associated with POLE p.Arg1382His (c.4145G>A)?

POLE p.Arg1382His (c.4145G>A) is associated with facial dysmorphism-immunodeficiency-livedo-short stature syndrome, colorectal cancer, susceptibility to, 12, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Arg1382His (c.4145G>A) in the general population?

POLE p.Arg1382His (c.4145G>A) is ultra-rare (popmax 0.0401%, amr) (gnomAD).

What do computational predictors say about POLE p.Arg1382His (c.4145G>A)?

AlphaMissense predicts likely benign (score 0.1021) — an in-silico prediction, not a clinical call.

POLE p.Arg1382His

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.

c.4145G>A · rs143229302 · VCV405766

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1021 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

facial dysmorphism-immunodeficiency-livedo-short stature syndrome

Computational evidence

Protein change
AlphaMissense	0.1021	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -9.25	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 2.2	GERP 1.5, phastCons 0.97
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	21.8	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 0.0401% Admixed American · 24/59,852 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0235%

Overall 0.00391% 63/1,611,214 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0401%	2,494
African / African-American	0.00534%	18,724
European (non-Finnish)	0.00297%	33,663

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.Arg1382His
Coding: c.4145G>A
MANE Select: NM_006231
dbSNP: rs143229302
Type: single nucleotide variant
Location: chr12:132648933 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1382: a UniProt-annotated variant site (in imagei); a UniProt-annotated variant site (found in a colorectal sample; somatic mutation)

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: colorectal cancer, susceptibility to, 12 hereditary neoplastic syndrome

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

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

POLE p.Arg1382Cys Uncertain significance ★★ ⚠ same residue
POLE p.Arg1382Leu Uncertain significance ★★ ⚠ same residue
POLE p.Arg1382= Likely benign ★★ same residue
POLE p.Arg1382Gly Uncertain significance ★ ⚠ same residue
POLE p.Arg1382Ser 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

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-arg1382his (accessed [today's date]).

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