Is POLE p.Val1270Phe (c.3808G>T) pathogenic?

POLE p.Val1270Phe (c.3808G>T) is classified Likely benign in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-28). AlphaMissense: likely benign (0.1696); Rare (popmax 0.158%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Val1270Phe (c.3808G>T)?

POLE p.Val1270Phe (c.3808G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Val1270Phe (c.3808G>T) in the general population?

POLE p.Val1270Phe (c.3808G>T) is rare (popmax 0.158%, eas) (gnomAD).

What do computational predictors say about POLE p.Val1270Phe (c.3808G>T)?

AlphaMissense predicts likely benign (score 0.1696) — an in-silico prediction, not a clinical call.

POLE p.Val1270Phe

c.3808G>T · VCV3422156

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1696 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.158%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1696	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -8.76	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 1.8	GERP 1.7, phastCons 0.93
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	21.6	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 0.158% East Asian · 70/44,296 alleles

Filtering AF 0.128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.117%

Overall 0.0116% 186/1,606,388 alleles · rare exomes 186/1,454,088 · genomes 0/152,300 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.158%	633
Admixed American	0.0938%	1,066
Finnishnot grpmax-eligible	0.0441%	2,269
Middle Eastern	0.0179%	5,576
Ashkenazi Jewishnot grpmax-eligible	0.0102%	9,781
Remaining individualsnot grpmax-eligible	0.00643%	15,552
South Asian	0.00551%	18,151
African / African-American	0.00267%	37,393
European (non-Finnish)	0.00161%	62,031

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.Val1270Phe
Coding: c.3808G>T
MANE Select: NM_006231
Type: single nucleotide variant
Location: chr12:132649503 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1270: 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

Similar variants

POLE p.Val1270Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely 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
POLE c.1106+4A>G Uncertain significance ★★ same condition
POLE c.1226+3A>G Uncertain significance ★★ same condition
POLE c.1359+4C>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-val1270phe (accessed [today's date]).

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