Is POLD1 p.Pro72= (c.216A>G) pathogenic?

POLD1 p.Pro72= (c.216A>G) is classified Likely benign in POLD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-13). Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLD1 p.Pro72= (c.216A>G)?

POLD1 p.Pro72= (c.216A>G) is associated with hereditary neoplastic syndrome, POLD1-related polyposis and colorectal cancer syndrome (ClinVar).

How common is POLD1 p.Pro72= (c.216A>G) in the general population?

POLD1 p.Pro72= (c.216A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

POLD1 p.Pro72=

c.216A>G · rs767196391 · VCV1135203

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary neoplastic 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 -5.5	GERP -2.3
Overall
CADD	0.135	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,884 alleles

Overall 6.2e-05% 1/1,613,740 alleles · very rare exomes 1/1,461,454 · genomes 0/152,286 · 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.Pro72=
Coding: c.216A>G
MANE Select: NM_002691
dbSNP: rs767196391
Type: single nucleotide variant
Location: chr19:50399384 (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

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

Also linked: POLD1-related polyposis and colorectal cancer syndrome

Similar variants

POLD1 p.Pro72Leu 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
POLD1 c.1383+1G>A Uncertain significance ★★ same condition
POLD1 c.1383+1G>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/pold1-p-pro72 (accessed [today's date]).

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