Is POLD1 p.Arg331= (c.993G>A) pathogenic?

POLD1 p.Arg331= (c.993G>A) is classified Benign/Likely benign in POLD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-05). No allele count reported in gnomAD v4.1 (AN 1,562,622); Associated with POLD1-related polyposis and colorectal cancer syndrome.

How common is POLD1 p.Arg331= (c.993G>A) in the general population?

POLD1 p.Arg331= (c.993G>A) is no allele count reported in gnomAD v4.1 (AN 1,562,622) (gnomAD).

How is Polymerase proofreading-related polyposis inherited?

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

POLD1 p.Arg331=

Q: What condition is associated with POLD1 p.Arg331= (c.993G>A)?

POLD1 p.Arg331= (c.993G>A) is associated with POLD1-related polyposis and colorectal cancer syndrome, hereditary neoplastic syndrome (ClinVar).

c.993G>A · rs2122268281 · VCV2448212

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,562,622)

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 1.7	GERP 0.017, phastCons 1
Overall
CADD	7.732	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,562,622). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: POLD1
Protein: p.Arg331=
Coding: c.993G>A
MANE Select: NM_002691
dbSNP: rs2122268281
Type: single nucleotide variant
Location: chr19:50403075 (GRCh38)
Gene constraint: LOEUF 0.878 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 86.93 · 6 PDB
Residue 331: a turn

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.Arg331Trp Uncertain significance ★★ ⚠ same residue
POLD1 p.Arg331Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
POLD1 p.Arg331Pro Uncertain significance ★ ⚠ same residue
POLD1 p.Arg331fs 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

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-arg331 (accessed [today's date]).

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