Is POLG p.Arg102Ser (c.304C>A) pathogenic?

POLG p.Arg102Ser (c.304C>A) is classified Uncertain significance in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). AlphaMissense: likely benign (0.2879); No allele count reported in gnomAD v4.1 (AN 1,610,456); Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Arg102Ser (c.304C>A)?

POLG p.Arg102Ser (c.304C>A) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Arg102Ser (c.304C>A) in the general population?

POLG p.Arg102Ser (c.304C>A) is no allele count reported in gnomAD v4.1 (AN 1,610,456) (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.Arg102Ser (c.304C>A)?

AlphaMissense predicts likely benign (score 0.2879) — an in-silico prediction, not a clinical call.

POLG p.Arg102Ser

c.304C>A · rs1328607569 · VCV944038

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2879 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,610,456)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

mitochondrial DNA depletion syndrome 4a

Computational evidence

Protein change
AlphaMissense	0.2879	likely benign
REVEL	0.515	indeterminate
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.7	GERP 0.98, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	24.2	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

No allele count reported in gnomAD v4.1 (AN 1,610,456). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: POLG
Protein: p.Arg102Ser
Coding: c.304C>A
MANE Select: NM_001430120 · reported on NM_002693
dbSNP: rs1328607569
Type: single nucleotide variant
Location: chr15:89333451 (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-arg102ser (accessed [today's date]).

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