Is POLD1 p.Pro7= (c.21A>G) pathogenic?

POLD1 p.Pro7= (c.21A>G) is classified Likely benign in POLD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-26). Very rare (popmax 8.48e-05%, nfe); Associated with POLD1-related polyposis and colorectal cancer syndrome.

What condition is associated with POLD1 p.Pro7= (c.21A>G)?

POLD1 p.Pro7= (c.21A>G) is associated with POLD1-related polyposis and colorectal cancer syndrome (ClinVar).

How common is POLD1 p.Pro7= (c.21A>G) in the general population?

POLD1 p.Pro7= (c.21A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Polymerase proofreading-related polyposis inherited?

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

POLD1 p.Pro7=

c.21A>G · rs1601188517 · VCV756889

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

POLD1-related polyposis and colorectal cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.91	GERP -2.1
Overall
CADD	7.481	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,178,880 alleles

Overall 6.22e-05% 1/1,608,520 alleles · very rare exomes 1/1,456,152 · genomes 0/152,368 · 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.Pro7=
Coding: c.21A>G
MANE Select: NM_002691
dbSNP: rs1601188517
Type: single nucleotide variant
Location: chr19:50398872 (GRCh38)
Gene constraint: LOEUF 0.878 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 86.93 · 6 PDB
Residue 7: the 'disordered' region

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

Disease context

POLD1-related polyposis and colorectal cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Polymerase proofreading-related polyposis (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

POLD1 p.Pro7Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
POLD1 p.Pro7Ser Benign ★ 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
POLD1 c.1383+1G>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/pold1-p-pro7 (accessed [today's date]).

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