Is POLG p.Pro960Ser (c.2878C>T) pathogenic?

POLG p.Pro960Ser (c.2878C>T) is classified Conflicting classifications of pathogenicity in POLG (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-05-21). AlphaMissense: likely benign (0.1057); Very rare (popmax 0.00576%, nfe); Associated with POLG-related disorder.

What condition is associated with POLG p.Pro960Ser (c.2878C>T)?

POLG p.Pro960Ser (c.2878C>T) is associated with POLG-related disorder, mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Pro960Ser (c.2878C>T) in the general population?

POLG p.Pro960Ser (c.2878C>T) is very rare (popmax 0.00576%, nfe) (gnomAD).

What do computational predictors say about POLG p.Pro960Ser (c.2878C>T)?

AlphaMissense predicts likely benign (score 0.1057) — an in-silico prediction, not a clinical call.

POLG p.Pro960Ser

c.2878C>T · rs373298169 · VCV594839

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1057 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00576%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

POLG-related disorder

Computational evidence

Protein change
AlphaMissense	0.1057	likely benign
REVEL	0.355	indeterminate
SaProt	LLR -4.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.95, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 4,387 bp · p 0.15 · regional, not allelic
Overall
CADD	20.7	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 0.00576% European (non-Finnish) · 68/1,180,050 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00422%

Overall 0.00471% 76/1,613,838 alleles · very rare exomes 67/1,461,628 · genomes 9/152,210 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
European (non-Finnish)grpmax	0.00576%	17,354
Remaining individualsnot grpmax-eligible	0.0016%	62,482

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro960Ser
Coding: c.2878C>T
MANE Select: NM_002693
dbSNP: rs373298169
Type: single nucleotide variant
Location: chr15:89320869 (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

Also linked: mitochondrial DNA depletion syndrome 4a

Similar variants

POLG p.Pro960= 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-pro960ser (accessed [today's date]).

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