Is POLG p.Ser63Phe (c.188C>T) pathogenic?

POLG p.Ser63Phe (c.188C>T) is classified Uncertain significance in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-06). AlphaMissense: likely benign (0.1197); Very rare (popmax 0.00167%, amr); Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Ser63Phe (c.188C>T)?

POLG p.Ser63Phe (c.188C>T) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Ser63Phe (c.188C>T) in the general population?

POLG p.Ser63Phe (c.188C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Alpers-Huttenlocher syndrome inherited?

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

What do computational predictors say about POLG p.Ser63Phe (c.188C>T)?

AlphaMissense predicts likely benign (score 0.1197) — an in-silico prediction, not a clinical call.

POLG p.Ser63Phe

c.188C>T · rs960812250 · VCV1485064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1197 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial DNA depletion syndrome 4a

Computational evidence

Protein change
AlphaMissense	0.1197	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -8.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.71	GERP 1.8, phastCons 0.99
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,928 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000559% 9/1,610,798 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,928
European (non-Finnish)	0.000679%	147,375

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.Ser63Phe
Coding: c.188C>T
MANE Select: NM_001430120 · reported on NM_002693
dbSNP: rs960812250
Type: single nucleotide variant
Location: chr15:89333567 (GRCh38)

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

Disease context

mitochondrial DNA depletion syndrome 4a — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alpers-Huttenlocher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Europe)

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-ser63phe (accessed [today's date]).

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