Is POLQ p.Phe1665= (c.4995T>C) pathogenic?

POLQ p.Phe1665= (c.4995T>C) is classified Conflicting classifications of pathogenicity in POLQ (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-02-12). Rare (popmax 0.301%, eas); Associated with POLQ-related disorder.

What condition is associated with POLQ p.Phe1665= (c.4995T>C)?

POLQ p.Phe1665= (c.4995T>C) is associated with POLQ-related disorder (ClinVar).

How common is POLQ p.Phe1665= (c.4995T>C) in the general population?

POLQ p.Phe1665= (c.4995T>C) is rare (popmax 0.301%, eas) (gnomAD).

POLQ p.Phe1665=

c.4995T>C · rs576293240 · VCV1744616

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.301%, eas)

Conditions

POLQ-related disorder

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 -2.2	GERP -3.4
Overall
CADD	0.259	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.301% East Asian · 135/44,834 alleles

Filtering AF 0.26% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.244%

Overall 0.00905% 145/1,602,928 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.301%	332
Remaining individualsnot grpmax-eligible	0.0145%	6,888
South Asian	0.00113%	88,266

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.Phe1665=
Coding: c.4995T>C
MANE Select: NM_016218 · reported on NM_199420
dbSNP: rs576293240
Type: single nucleotide variant
Location: chr3:121487936 (GRCh38)
Structure: AlphaFold pLDDT 70.62 · 19 PDB

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

Disease context

POLQ-related disorder

Similar variants

POLQ p.Phe1665Val Uncertain significance ★ ⚠ same residue
POLQ p.Arg2169Cys Uncertain significance ★★ ⚠ same condition
POLQ p.Arg2347Cys Uncertain significance ★★ ⚠ same condition
POLQ p.Cys2219Tyr Uncertain significance ★★ ⚠ same condition
POLQ p.Glu2246Lys Uncertain significance ★★ ⚠ same condition
POLQ p.Glu731Ala Uncertain significance ★★ ⚠ same condition
POLQ p.Lys68Glu Uncertain significance ★★ ⚠ same condition
POLQ p.Met1707Val 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/polq-p-phe1665 (accessed [today's date]).

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