What do computational predictors say about POLE p.Ala252Val (c.755C>T)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

POLE p.Ala252Val

Q: Is POLE p.Ala252Val (c.755C>T) pathogenic?

POLE p.Ala252Val (c.755C>T) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0769); Common (popmax 11%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency.

Q: What condition is associated with POLE p.Ala252Val (c.755C>T)?

POLE p.Ala252Val (c.755C>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).

Q: How common is POLE p.Ala252Val (c.755C>T) in the general population?

POLE p.Ala252Val (c.755C>T) is common (popmax 11%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.755C>T · rs5744751 · VCV380210

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 11%, nfe) — too common for a highly-penetrant pathogenic allele

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	0.0769	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -5.01	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 9.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	20.6	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 11% European (non-Finnish) · 129,273/1,179,412 alleles

Filtering AF 10.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.9%

Overall 9.91% 159,920/1,613,392 alleles · common exomes 148,220/1,461,228 · genomes 11,700/152,164 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	20.6%	5
Ashkenazi Jewishnot grpmax-eligible	11.2%	9
European (non-Finnish)grpmax	11%	9
Finnishnot grpmax-eligible	10.8%	9
East Asian	10.8%	9
Remaining individualsnot grpmax-eligible	9.8%	10
Middle Eastern	6.77%	15
South Asian	5.32%	19
Admixed American	4.6%	22
African / African-American	1.66%	60

Amish 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.Ala252Val
Coding: c.755C>T
MANE Select: NM_006231
dbSNP: rs5744751
Type: single nucleotide variant
Location: chr12:132677409 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 252: a UniProt-annotated variant site (in); a β-strand

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.Ala252Pro Uncertain significance ★★ ⚠ same residue
POLE p.Ala252Ser Uncertain significance ★ ⚠ same residue
POLE p.Ala252Thr Uncertain significance ★ ⚠ same residue
POLE p.Ala252Gly Uncertain significance ★ ⚠ same residue
POLE p.Ala252= 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

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-ala252val (accessed [today's date]).

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