Is POLG2 p.Ser424Pro (c.1270T>C) pathogenic?

POLG2 p.Ser424Pro (c.1270T>C) is classified Uncertain significance in POLG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-02). AlphaMissense: likely benign (0.1349); Very rare (popmax 0.00168%, amr).

How common is POLG2 p.Ser424Pro (c.1270T>C) in the general population?

POLG2 p.Ser424Pro (c.1270T>C) is very rare (popmax 0.00168%, amr) (gnomAD).

What do computational predictors say about POLG2 p.Ser424Pro (c.1270T>C)?

AlphaMissense predicts likely benign (score 0.1349) — an in-silico prediction, not a clinical call.

POLG2 p.Ser424Pro

c.1270T>C · rs2037835912 · VCV1318801

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1349 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1349	likely benign
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -7.50	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.98 · regional, not allelic
Overall
CADD	23.5	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 0.00168% Admixed American · 1/59,578 alleles

Filtering AF 0.000255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000164%

Overall 0.000509% 8/1,571,290 alleles · very rare exomes 7/1,419,066 · genomes 1/152,224 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,578
European (non-Finnish)	0.000612%	163,365

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.Ser424Pro
Coding: c.1270T>C
MANE Select: NM_007215
dbSNP: rs2037835912
Type: single nucleotide variant
Location: chr17:64480311 (GRCh38)
Gene constraint: LOEUF 1.156 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.73 · 38 PDB

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

Similar variants

POLG2 p.Ala209Ser Uncertain significance ★★ ⚠ same type
POLG2 p.Ala9Val Uncertain significance ★★ ⚠ same type
POLG2 p.Arg122Ser Uncertain significance ★★ same type
POLG2 p.Arg284Gln Uncertain significance ★★ ⚠ same type
POLG2 p.Cys16Ser Uncertain significance ★★ ⚠ same type
POLG2 p.Glu123Lys Uncertain significance ★★ ⚠ same type
POLG2 p.Gly103Val Uncertain significance ★★ ⚠ same type
POLG2 p.Gly188Arg 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/polg2-p-ser424pro (accessed [today's date]).

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