Is POLB p.Phe200Val (c.598T>G) pathogenic?

POLB p.Phe200Val (c.598T>G) is classified Uncertain significance in POLB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely pathogenic (0.6733); Ultra-rare (popmax 0.0164%, mid).

How common is POLB p.Phe200Val (c.598T>G) in the general population?

POLB p.Phe200Val (c.598T>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about POLB p.Phe200Val (c.598T>G)?

AlphaMissense predicts likely pathogenic (score 0.6733) — an in-silico prediction, not a clinical call.

POLB p.Phe200Val

c.598T>G · rs745652653 · VCV3216305

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6733 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6733	likely pathogenic
REVEL	0.374	indeterminate
SaProt	LLR -11.74	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 22 kb · p 0.0028 · regional, not allelic
Overall
CADD	23.3	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00318%

Overall 0.00354% 57/1,612,114 alleles · ultra-rare exomes 54/1,459,890 · genomes 3/152,224 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Remaining individualsnot grpmax-eligible	0.0048%	20,812
European (non-Finnish)	0.0045%	22,230

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.Phe200Val
Coding: c.598T>G
MANE Select: NM_002690
dbSNP: rs745652653
Type: single nucleotide variant
Location: chr8:42361342 (GRCh38)
Gene constraint: LOEUF 1.772 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 94.30 · 435 PDB
Residue 200: 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.Arg254Ile 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

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-phe200val (accessed [today's date]).

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