Is POLE p.Pro1549Ala (c.4645C>G) pathogenic?

POLE p.Pro1549Ala (c.4645C>G) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0478); Rare (popmax 0.14%, amr); Associated with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency.

How common is POLE p.Pro1549Ala (c.4645C>G) in the general population?

POLE p.Pro1549Ala (c.4645C>G) is rare (popmax 0.14%, amr) (gnomAD).

What do computational predictors say about POLE p.Pro1549Ala (c.4645C>G)?

AlphaMissense predicts likely benign (score 0.0478) — an in-silico prediction, not a clinical call.

POLE p.Pro1549Ala

Q: What condition is associated with POLE p.Pro1549Ala (c.4645C>G)?

POLE p.Pro1549Ala (c.4645C>G) 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.4645C>G · rs147500308 · VCV240531

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.0478 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.14%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Computational evidence

Protein change
AlphaMissense	0.0478	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -5.46	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 1.1	GERP -0.57, phastCons 0.48
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	3.091	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 0.14% Admixed American · 84/59,920 alleles

Filtering AF 0.116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.107%

Overall 0.0198% 319/1,613,720 alleles · rare exomes 280/1,461,366 · genomes 39/152,354 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.14%	713
Middle Eastern	0.0496%	2,016
Remaining individualsnot grpmax-eligible	0.0416%	2,403
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,287
African / African-American	0.0293%	3,411
European (non-Finnish)	0.0147%	6,781
South Asian	0.0011%	91,052

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.Pro1549Ala
Coding: c.4645C>G
MANE Select: NM_006231
dbSNP: rs147500308
Type: single nucleotide variant
Location: chr12:132642903 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1549: 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: colorectal cancer, susceptibility to, 12 facial dysmorphism-immunodeficiency-livedo-short stature syndrome hereditary neoplastic syndrome

Similar variants

POLE p.Pro1549= Likely benign ★★ same residue
POLE p.Pro1549Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro1549His Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro1549Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro1549Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro1549Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T 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-pro1549ala (accessed [today's date]).

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