Is POLB p.Ala185Thr (c.553G>A) pathogenic?

POLB p.Ala185Thr (c.553G>A) is classified Uncertain significance in POLB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-13). AlphaMissense: likely benign (0.2718); Absent from gnomAD v4.1.

How common is POLB p.Ala185Thr (c.553G>A) in the general population?

POLB p.Ala185Thr (c.553G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POLB p.Ala185Thr (c.553G>A)?

AlphaMissense predicts likely benign (score 0.2718) — an in-silico prediction, not a clinical call.

POLB p.Ala185Thr

c.553G>A · VCV3308264

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2718 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,608,586)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2718	likely benign
REVEL	0.437	indeterminate
SaProt	LLR -9.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 22 kb · p 0.0028 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

No allele count reported in gnomAD v4.1 (AN 1,608,586). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: POLB
Protein: p.Ala185Thr
Coding: c.553G>A
MANE Select: NM_002690
Type: single nucleotide variant
Location: chr8:42361297 (GRCh38)
Gene constraint: LOEUF 1.772 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 94.30 · 435 PDB
Residue 185: the 'dna-binding' region

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

Similar variants

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
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-ala185thr (accessed [today's date]).

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