Is POLG p.Pro960= (c.2880C>T) pathogenic?

POLG p.Pro960= (c.2880C>T) is classified Conflicting classifications of pathogenicity in POLG (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-13). Ultra-rare (popmax 0.0153%, nfe); Associated with hereditary spastic paraplegia.

What condition is associated with POLG p.Pro960= (c.2880C>T)?

POLG p.Pro960= (c.2880C>T) is associated with hereditary spastic paraplegia, mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Pro960= (c.2880C>T) in the general population?

POLG p.Pro960= (c.2880C>T) is ultra-rare (popmax 0.0153%, nfe) (gnomAD).

POLG p.Pro960=

c.2880C>T · rs752500492 · VCV378415

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0153%, nfe)

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.089	GERP -3.8, phastCons 0.67
Overall
CADD	6.078	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0153% European (non-Finnish) · 181/1,180,030 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.0115% 186/1,613,850 alleles · ultra-rare exomes 179/1,461,646 · genomes 7/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0153%	6,519
Remaining individualsnot grpmax-eligible	0.0048%	20,827
African / African-American	0.00267%	37,467

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.Pro960=
Coding: c.2880C>T
MANE Select: NM_002693
dbSNP: rs752500492
Type: single nucleotide variant
Location: chr15:89320867 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 960: an α-helix

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

Disease context

hereditary spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial DNA depletion syndrome 4a

Similar variants

POLG p.Pro960Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
POLG c.3643+2T>C Pathogenic ★★★ same condition
POLG p.Ala1105Pro Likely pathogenic ★★★ same condition
POLG p.Arg1096Cys Likely pathogenic ★★★ same condition
POLG p.Asp1184Asn Pathogenic ★★★ same condition
POLG p.Gln1175Ter Likely pathogenic ★★★ same condition
POLG p.Lys1191Asn Likely pathogenic ★★★ same condition
POLG c.3483-14T>C 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-pro960 (accessed [today's date]).

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