Is POLQ p.Arg533Pro (c.1598G>C) pathogenic?

POLQ p.Arg533Pro (c.1598G>C) is classified Uncertain significance in POLQ (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-10). AlphaMissense: likely pathogenic (0.9654); Very rare (popmax 0.00017%, nfe).

How common is POLQ p.Arg533Pro (c.1598G>C) in the general population?

POLQ p.Arg533Pro (c.1598G>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about POLQ p.Arg533Pro (c.1598G>C)?

AlphaMissense predicts likely pathogenic (score 0.9654) — an in-silico prediction, not a clinical call.

POLQ p.Arg533Pro

c.1598G>C · rs375451342 · VCV1776044

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9654 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9654	likely pathogenic · top 5% in POLQ
REVEL	0.447	indeterminate
SaProt	LLR -11.76	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,634 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,098 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,020
European (non-Finnish)grpmax	0.00017%	589,817

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: POLQ
Protein: p.Arg533Pro
Coding: c.1598G>C
MANE Select: NM_016218 · reported on NM_199420
dbSNP: rs375451342
Type: single nucleotide variant
Location: chr3:121511900 (GRCh38)
Structure: AlphaFold pLDDT 70.62 · 19 PDB

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

Similar variants

POLQ p.Arg533Leu Uncertain significance ★ ⚠ same residue
POLQ p.Arg2169Cys Uncertain significance ★★ ⚠ same type
POLQ p.Arg2347Cys Uncertain significance ★★ ⚠ same type
POLQ p.Cys2219Tyr Uncertain significance ★★ ⚠ same type
POLQ p.Glu2246Lys Uncertain significance ★★ ⚠ same type
POLQ p.Glu731Ala Uncertain significance ★★ ⚠ same type
POLQ p.Lys68Glu Uncertain significance ★★ ⚠ same type
POLQ p.Met1707Val Uncertain significance ★★ ⚠ same type

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/polq-p-arg533pro (accessed [today's date]).

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