Is POLD1 p.Pro110Ser (c.328C>T) pathogenic?

POLD1 p.Pro110Ser (c.328C>T) is classified Conflicting classifications of pathogenicity in POLD1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0812); Very rare (popmax 0.00551%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLD1 p.Pro110Ser (c.328C>T)?

POLD1 p.Pro110Ser (c.328C>T) is associated with hereditary neoplastic syndrome, POLD1-related polyposis and colorectal cancer syndrome (ClinVar).

How common is POLD1 p.Pro110Ser (c.328C>T) in the general population?

POLD1 p.Pro110Ser (c.328C>T) is very rare (popmax 0.00551%, nfe) (gnomAD).

What do computational predictors say about POLD1 p.Pro110Ser (c.328C>T)?

AlphaMissense predicts likely benign (score 0.0812) — an in-silico prediction, not a clinical call.

POLD1 p.Pro110Ser

c.328C>T · rs531059492 · VCV408046

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0812 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00551%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0812	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -8.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.079	GERP -2.5
Regional constraint	o/e 1.05	unconstrained · MANE · 3,425 bp · p 0.36 · regional, not allelic
Overall
CADD	1.166	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

Grpmax group 0.00551% European (non-Finnish) · 65/1,179,820 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00403%

Overall 0.00521% 84/1,612,602 alleles · very rare exomes 79/1,460,352 · genomes 5/152,250 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0287%	3,488
European (non-Finnish)grpmax	0.00551%	18,151
Remaining individualsnot grpmax-eligible	0.0016%	62,474

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro110Ser
Coding: c.328C>T
MANE Select: NM_002691
dbSNP: rs531059492
Type: single nucleotide variant
Location: chr19:50401789 (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.Pro110Arg Uncertain significance ★★ ⚠ same residue
POLD1 p.Pro110Leu Uncertain significance ★ ⚠ same residue
POLD1 p.Pro110= Likely benign ★ same residue
POLD1 p.Pro110fs 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-pro110ser (accessed [today's date]).

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