Is POLG p.Pro648Ser (c.1942C>T) pathogenic?

POLG p.Pro648Ser (c.1942C>T) is classified Likely pathogenic in POLG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-17). AlphaMissense: likely pathogenic (0.7438); Absent from gnomAD v4.1; Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Pro648Ser (c.1942C>T)?

POLG p.Pro648Ser (c.1942C>T) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Pro648Ser (c.1942C>T) in the general population?

POLG p.Pro648Ser (c.1942C>T) is absent from gnomAD v4.1 (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.Pro648Ser (c.1942C>T)?

AlphaMissense predicts likely pathogenic (score 0.7438) — an in-silico prediction, not a clinical call.

POLG p.Pro648Ser

c.1942C>T · rs2055502246 · VCV2813186

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7438 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial DNA depletion syndrome 4a

Computational evidence

Protein change
AlphaMissense	0.7438	likely pathogenic ✓ concordant with ClinVar
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -3.18	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	26.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: POLG
Protein: p.Pro648Ser
Coding: c.1942C>T
MANE Select: NM_002693
dbSNP: rs2055502246
Type: single nucleotide variant
Location: chr15:89325457 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB
Residue 648: a turn; a UniProt-annotated variant site (in peob1; sporadic case; also in sando)

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)

Similar variants

POLG p.Pro648Arg Pathogenic/Likely pathogenic ★★ ⚠ 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-pro648ser (accessed [today's date]).

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