Is POLE p.Glu978Asp (c.2934A>C) pathogenic?

POLE p.Glu978Asp (c.2934A>C) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-22). AlphaMissense: likely pathogenic (0.9935); Very rare (popmax 0.00269%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Glu978Asp (c.2934A>C)?

POLE p.Glu978Asp (c.2934A>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Glu978Asp (c.2934A>C) in the general population?

POLE p.Glu978Asp (c.2934A>C) is very rare (popmax 0.00269%, afr) (gnomAD).

What do computational predictors say about POLE p.Glu978Asp (c.2934A>C)?

AlphaMissense predicts likely pathogenic (score 0.9935) — an in-silico prediction, not a clinical call.

POLE p.Glu978Asp

c.2934A>C · rs2042669492 · VCV1797847

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00269%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9935	likely pathogenic · top 7% in POLE
REVEL	0.348	indeterminate
SaProt	LLR -13.48	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.024	GERP -2.2, phastCons 0.76
Regional constraint	o/e 0.37	unconstrained · MANE · 123 bp · p 5.9e-06 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00269% African / African-American · 2/74,368 alleles

Filtering AF 0.00183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00158%

Overall 0.00225% 36/1,596,878 alleles · very rare exomes 34/1,446,038 · genomes 2/150,840 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00269%	37,184
European (non-Finnish)	0.00257%	38,872
East Asian	0.00225%	44,404
Admixed American	0.00167%	59,788
Remaining individualsnot grpmax-eligible	0.00162%	61,774
Finnishnot grpmax-eligible	0.00158%	63,372

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.Glu978Asp
Coding: c.2934A>C
MANE Select: NM_006231
dbSNP: rs2042669492
Type: single nucleotide variant
Location: chr12:132661095 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 978: a β-strand; 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.Glu978Lys Uncertain significance ★ ⚠ same residue
POLE p.Glu978Ter Conflicting classifications of pathogenicity ★ same residue
POLE p.Glu978= Likely benign ★ same residue
POLE p.Glu978fs 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

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-glu978asp (accessed [today's date]).

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