Is POLG p.Pro166His (c.497C>A) pathogenic?

POLG p.Pro166His (c.497C>A) is classified Uncertain significance in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). AlphaMissense: likely pathogenic (0.8531); Very rare (popmax 0.00026%, nfe); Associated with Inborn genetic diseases.

What condition is associated with POLG p.Pro166His (c.497C>A)?

POLG p.Pro166His (c.497C>A) is associated with Inborn genetic diseases (ClinVar).

How common is POLG p.Pro166His (c.497C>A) in the general population?

POLG p.Pro166His (c.497C>A) is very rare (popmax 0.00026%, nfe) (gnomAD).

What do computational predictors say about POLG p.Pro166His (c.497C>A)?

AlphaMissense predicts likely pathogenic (score 0.8531) — an in-silico prediction, not a clinical call.

POLG p.Pro166His

c.497C>A · VCV3935817

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8531 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00026%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8531	likely pathogenic
REVEL	0.801	moderately pathogenic-leaning
SaProt	LLR -17.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	26.5	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 0.00026% European (non-Finnish) · 3/1,154,630 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000192% 3/1,566,088 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: POLG
Protein: p.Pro166His
Coding: c.497C>A
MANE Select: NM_002693
Type: single nucleotide variant
Location: chr15:89333258 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 166: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POLG p.Pro166Ser Uncertain significance ★ ⚠ same residue
POLG p.Arg597Trp Pathogenic/Likely pathogenic ★★ same condition
POLG p.Gln137Ter Pathogenic/Likely pathogenic ★★ same condition
POLG p.Ser305Arg Pathogenic/Likely pathogenic ★★ same condition
POLG c.2481-4C>G Uncertain significance ★★ same condition
POLG p.Ala154Thr Uncertain significance ★★ ⚠ same condition
POLG p.Ala184Val Uncertain significance ★★ ⚠ same condition
POLG p.Ala915Thr 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/polg-p-pro166his (accessed [today's date]).

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