Is POLE p.Arg52Trp (c.154C>T) pathogenic?

POLE p.Arg52Trp (c.154C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2026-01-21). AlphaMissense: ambiguous (0.5078); Ultra-rare (popmax 0.02%, amr); Associated with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency.

How common is POLE p.Arg52Trp (c.154C>T) in the general population?

POLE p.Arg52Trp (c.154C>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about POLE p.Arg52Trp (c.154C>T)?

AlphaMissense predicts ambiguous (score 0.5078) — an in-silico prediction, not a clinical call.

POLE p.Arg52Trp

Q: What condition is associated with POLE p.Arg52Trp (c.154C>T)?

POLE p.Arg52Trp (c.154C>T) 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.154C>T · rs115452881 · VCV240396

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

AlphaMissense

ambiguous

0.5078 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.5078	ambiguous
REVEL	0.329	indeterminate
SaProt	LLR -12.32	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -0.58, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	23.8	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 0.02% Admixed American · 12/60,000 alleles

Filtering AF 0.0117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0111%

Overall 0.0126% 204/1,614,026 alleles · ultra-rare exomes 180/1,461,854 · genomes 24/152,172 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0272%	3,677
Admixed Americangrpmax	0.02%	5,000
European (non-Finnish)	0.0135%	7,421
Finnishnot grpmax-eligible	0.0109%	9,139
African / African-American	0.008%	12,499
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asian	0.0022%	45,537

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg52Trp
Coding: c.154C>T
MANE Select: NM_006231
dbSNP: rs115452881
Type: single nucleotide variant
Location: chr12:132681188 (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

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 familial colorectal cancer type X Polymerase proofreading-related adenomatous polyposis

Similar variants

POLE p.Arg52Leu Uncertain significance ★★ ⚠ same residue
POLE p.Arg52Pro Uncertain significance ★★ ⚠ same residue
POLE p.Arg52Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Arg52= Likely benign ★ 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

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-arg52trp (accessed [today's date]).

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