Is POLE p.Ala399Val (c.1196C>T) pathogenic?

POLE p.Ala399Val (c.1196C>T) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-08). AlphaMissense: ambiguous (0.4346); Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ala399Val (c.1196C>T)?

POLE p.Ala399Val (c.1196C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ala399Val (c.1196C>T) in the general population?

POLE p.Ala399Val (c.1196C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about POLE p.Ala399Val (c.1196C>T)?

AlphaMissense predicts ambiguous (score 0.4346) — an in-silico prediction, not a clinical call.

POLE p.Ala399Val

c.1196C>T · rs1060500853 · VCV405798

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4346 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4346	ambiguous
REVEL	0.115	moderately benign-leaning
SaProt	LLR -7.65	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	25.4	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 0.00133% African / African-American · 1/75,052 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000547% 8/1,461,832 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,052
European (non-Finnish)	0.000593%	168,576

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.Ala399Val
Coding: c.1196C>T
MANE Select: NM_006231
dbSNP: rs1060500853
Type: single nucleotide variant
Location: chr12:132675428 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POLE p.Ala399Thr Uncertain significance ★ ⚠ same residue
POLE p.Ala399= Benign/Likely benign ★★ same residue
POLE p.Ala399Pro Uncertain significance ★ ⚠ 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

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-ala399val (accessed [today's date]).

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