Is POLD1 p.Arg331Pro (c.992G>C) pathogenic?

POLD1 p.Arg331Pro (c.992G>C) is classified Uncertain significance in POLD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-05-25). AlphaMissense: likely pathogenic (0.9329); No allele count reported in gnomAD v4.1 (AN 1,562,442); Associated with hereditary neoplastic syndrome.

What condition is associated with POLD1 p.Arg331Pro (c.992G>C)?

POLD1 p.Arg331Pro (c.992G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLD1 p.Arg331Pro (c.992G>C) in the general population?

POLD1 p.Arg331Pro (c.992G>C) is no allele count reported in gnomAD v4.1 (AN 1,562,442) (gnomAD).

What do computational predictors say about POLD1 p.Arg331Pro (c.992G>C)?

AlphaMissense predicts likely pathogenic (score 0.9329) — an in-silico prediction, not a clinical call.

POLD1 p.Arg331Pro

c.992G>C · rs371120096 · VCV486088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9329 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,562,442)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9329	likely pathogenic
REVEL	0.074	moderately benign-leaning
SaProt	LLR -13.45	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.6	GERP -1.3, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 13 kb · p 4.5e-19 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,562,442). 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.Arg331Pro
Coding: c.992G>C
MANE Select: NM_002691
dbSNP: rs371120096
Type: single nucleotide variant
Location: chr19:50403074 (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

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

Similar variants

POLD1 p.Arg331Trp Uncertain significance ★★ ⚠ same residue
POLD1 p.Arg331= Benign/Likely benign ★★ same residue
POLD1 p.Arg331Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
POLD1 p.Arg331fs Uncertain significance ★ same residue
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-arg331pro (accessed [today's date]).

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