Is POLG p.Pro166Ser (c.496C>T) pathogenic?

POLG p.Pro166Ser (c.496C>T) is classified Uncertain significance in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-03). AlphaMissense: likely pathogenic (0.7667); Very rare (popmax 0.00236%, eas); Associated with Inborn genetic diseases.

What condition is associated with POLG p.Pro166Ser (c.496C>T)?

POLG p.Pro166Ser (c.496C>T) is associated with Inborn genetic diseases (ClinVar).

How common is POLG p.Pro166Ser (c.496C>T) in the general population?

POLG p.Pro166Ser (c.496C>T) is very rare (popmax 0.00236%, eas) (gnomAD).

What do computational predictors say about POLG p.Pro166Ser (c.496C>T)?

AlphaMissense predicts likely pathogenic (score 0.7667) — an in-silico prediction, not a clinical call.

POLG p.Pro166Ser

c.496C>T · rs2509275191 · VCV2228339

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7667 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00236%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7667	likely pathogenic
REVEL	0.798	moderately pathogenic-leaning
SaProt	LLR -14.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 0.82, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	25.8	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 0.00236% East Asian · 1/42,444 alleles

Filtering AF 0.000367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000266%

Overall 0.000638% 10/1,566,430 alleles · very rare exomes 10/1,414,060 · genomes 0/152,370 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00236%	42,444
European (non-Finnish)	0.000779%	128,308

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.Pro166Ser
Coding: c.496C>T
MANE Select: NM_002693
dbSNP: rs2509275191
Type: single nucleotide variant
Location: chr15:89333259 (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.Pro166His 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-pro166ser (accessed [today's date]).

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