Is POLD1 p.Lys897= (c.2691G>A) pathogenic?

POLD1 p.Lys897= (c.2691G>A) is classified Likely benign in POLD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-04-20). Very rare (popmax 0.00267%, afr); Associated with POLD1-related polyposis and colorectal cancer syndrome.

How common is POLD1 p.Lys897= (c.2691G>A) in the general population?

POLD1 p.Lys897= (c.2691G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Polymerase proofreading-related polyposis inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

POLD1 p.Lys897=

Q: What condition is associated with POLD1 p.Lys897= (c.2691G>A)?

POLD1 p.Lys897= (c.2691G>A) is associated with POLD1-related polyposis and colorectal cancer syndrome, hereditary neoplastic syndrome (ClinVar).

c.2691G>A · rs1057522764 · VCV387353

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

POLD1-related polyposis and colorectal cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.57	donor loss · deltas
Constraint at this position
Conservation	phyloP 2.4	GERP -0.002, phastCons 1
Overall
CADD	8.674	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,926 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,612,264 alleles · very rare exomes 1/1,460,040 · genomes 1/152,224 · joint denominator

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: POLD1
Protein: p.Lys897=
Coding: c.2691G>A
MANE Select: NM_002691
dbSNP: rs1057522764
Type: single nucleotide variant
Location: chr19:50415564 (GRCh38)
Gene constraint: LOEUF 0.878 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 86.93 · 6 PDB

Full POLD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hereditary neoplastic syndrome

For Polymerase proofreading-related polyposis (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

POLD1 p.Lys897Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
POLD1 p.Lys897Gln Uncertain significance ★ ⚠ same residue
POLD1 p.Lys897fs Uncertain significance ★★ same residue
POLD1 p.Arg507Cys Likely pathogenic ★★ same condition
POLD1 p.Leu474Pro Pathogenic/Likely pathogenic ★★ same condition
POLD1 p.Ser478Asn Pathogenic/Likely pathogenic ★★ same condition
POLD1 c.1137+1G>A Uncertain significance ★★ same condition
POLD1 c.1137+3A>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/pold1-p-lys897 (accessed [today's date]).

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