Is POLG2 p.Ser178Phe (c.533C>T) pathogenic?

POLG2 p.Ser178Phe (c.533C>T) is classified Uncertain significance in POLG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-25). AlphaMissense: ambiguous (0.4484); Very rare (popmax 0.00404%, afr).

How common is POLG2 p.Ser178Phe (c.533C>T) in the general population?

POLG2 p.Ser178Phe (c.533C>T) is very rare (popmax 0.00404%, afr) (gnomAD).

What do computational predictors say about POLG2 p.Ser178Phe (c.533C>T)?

AlphaMissense predicts ambiguous (score 0.4484) — an in-silico prediction, not a clinical call.

POLG2 p.Ser178Phe

c.533C>T · rs782061130 · VCV1931664

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4484 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00404%, afr)

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.4484	ambiguous
REVEL	0.371	indeterminate
SaProt	LLR -12.99	damaging
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.5	GERP 1.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.98 · regional, not allelic
Overall
CADD	24.9	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 0.00404% African / African-American · 3/74,176 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000498%

Overall 0.000756% 12/1,587,776 alleles · very rare exomes 11/1,435,600 · genomes 1/152,176 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00404%	24,725
Admixed American	0.00343%	29,197
Remaining individualsnot grpmax-eligible	0.00327%	30,565
European (non-Finnish)	0.000431%	231,973

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: POLG2
Protein: p.Ser178Phe
Coding: c.533C>T
MANE Select: NM_007215
dbSNP: rs782061130
Type: single nucleotide variant
Location: chr17:64496436 (GRCh38)

Full POLG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/polg2-p-ser178phe (accessed [today's date]).

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