Is POLB p.Arg254Ile (c.761G>T) pathogenic?

POLB p.Arg254Ile (c.761G>T) is classified Uncertain significance in POLB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-12). AlphaMissense: likely pathogenic (0.9954); Very rare (popmax 0.000435%, nfe).

How common is POLB p.Arg254Ile (c.761G>T) in the general population?

POLB p.Arg254Ile (c.761G>T) is very rare (popmax 0.000435%, nfe) (gnomAD).

What do computational predictors say about POLB p.Arg254Ile (c.761G>T)?

AlphaMissense predicts likely pathogenic (score 0.9954) — an in-silico prediction, not a clinical call.

POLB p.Arg254Ile

c.761G>T · rs756393596 · VCV2318022

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000435%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9954	likely pathogenic · top 5% in POLB
REVEL	0.717	pathogenic-leaning
SaProt	LLR -16.65	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.32	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 22 kb · p 0.0028 · regional, not allelic
Overall
CADD	33.0	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 0.000435% European (non-Finnish) · 5/1,149,448 alleles

Filtering AF 0.000127% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.3e-05%

Overall 0.00035% 5/1,426,582 alleles · very rare

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: POLB
Protein: p.Arg254Ile
Coding: c.761G>T
MANE Select: NM_002690
dbSNP: rs756393596
Type: single nucleotide variant
Location: chr8:42369323 (GRCh38)
Gene constraint: LOEUF 1.772 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 94.30 · 435 PDB
Residue 254: a β-strand

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

Similar variants

POLB p.Ala185Thr Uncertain significance ★ ⚠ same type
POLB p.Ala23Ser Uncertain significance ★ ⚠ same type
POLB p.Glu129Gly Uncertain significance ★ ⚠ same type
POLB p.Glu316Lys Uncertain significance ★ ⚠ same type
POLB p.Glu335Lys Uncertain significance ★ ⚠ same type
POLB p.His212Tyr Uncertain significance ★ ⚠ same type
POLB p.Ile119Val Uncertain significance ★ ⚠ same type
POLB p.Lys248Glu 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/polb-p-arg254ile (accessed [today's date]).

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