Is POLG p.Pro116Ser (c.346C>T) pathogenic?

POLG p.Pro116Ser (c.346C>T) is classified Conflicting classifications of pathogenicity in POLG (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-01). AlphaMissense: likely benign (0.0888); Ultra-rare (popmax 0.0358%, eas); Associated with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis.

What condition is associated with POLG p.Pro116Ser (c.346C>T)?

POLG p.Pro116Ser (c.346C>T) is associated with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, mitochondrial DNA depletion syndrome 4a, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (ClinVar).

How common is POLG p.Pro116Ser (c.346C>T) in the general population?

POLG p.Pro116Ser (c.346C>T) is ultra-rare (popmax 0.0358%, eas) (gnomAD).

What do computational predictors say about POLG p.Pro116Ser (c.346C>T)?

AlphaMissense predicts likely benign (score 0.0888) — an in-silico prediction, not a clinical call.

POLG p.Pro116Ser

Q: How is Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.346C>T · rs771676521 · VCV206620

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0888 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0358%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

Computational evidence

Protein change
AlphaMissense	0.0888	likely benign
REVEL	0.31	indeterminate
SaProt	LLR -8.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -1.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	21.1	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 0.0358% East Asian · 16/44,696 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.000997% 16/1,604,396 alleles · ultra-rare exomes 12/1,452,128 · genomes 4/152,268 · joint denominator

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.Pro116Ser
Coding: c.346C>T
MANE Select: NM_002693
dbSNP: rs771676521
Type: single nucleotide variant
Location: chr15:89333409 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 116: a β-strand

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

Disease context

sensory ataxic neuropathy, dysarthria, and ophthalmoparesis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial DNA depletion syndrome 4a progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 mitochondrial DNA depletion syndrome 1 mitochondrial DNA depletion syndrome 4b progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

For Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult

Similar variants

POLG p.Pro116Arg Uncertain significance ★★ ⚠ same residue
POLG p.Pro116Gln Uncertain significance ★★ ⚠ same residue
POLG p.Pro116Leu Uncertain significance ★★ ⚠ same residue
POLG p.Pro116Thr Uncertain significance ★ ⚠ 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

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-pro116ser (accessed [today's date]).

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