Is POLB p.Glu335Lys (c.1003G>A) pathogenic?

POLB p.Glu335Lys (c.1003G>A) is classified Uncertain significance in POLB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: ambiguous (0.5161); Ultra-rare (popmax 0.0206%, nfe).

How common is POLB p.Glu335Lys (c.1003G>A) in the general population?

POLB p.Glu335Lys (c.1003G>A) is ultra-rare (popmax 0.0206%, nfe) (gnomAD).

What do computational predictors say about POLB p.Glu335Lys (c.1003G>A)?

AlphaMissense predicts ambiguous (score 0.5161) — an in-silico prediction, not a clinical call.

POLB p.Glu335Lys

c.1003G>A · rs200653703 · VCV2374564

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5161 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0206%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5161	ambiguous
REVEL	0.132	moderately benign-leaning
SaProt	LLR -6.51	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 22 kb · p 0.0028 · regional, not allelic
Overall
CADD	24.2	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 0.0206% European (non-Finnish) · 239/1,162,332 alleles

Filtering AF 0.0184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0175%

Overall 0.0159% 253/1,594,378 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0206%	4,863
Remaining individualsnot grpmax-eligible	0.0097%	10,304
African / African-American	0.00805%	12,420
South Asian	0.00221%	45,327

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.Glu335Lys
Coding: c.1003G>A
MANE Select: NM_002690
dbSNP: rs200653703
Type: single nucleotide variant
Location: chr8:42371652 (GRCh38)
Gene constraint: LOEUF 1.772 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 94.30 · 435 PDB

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.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-glu335lys (accessed [today's date]).

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