Is POLG p.Val201= (c.603C>T) pathogenic?

POLG p.Val201= (c.603C>T) is classified Conflicting classifications of pathogenicity in POLG (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-30). Ultra-rare (popmax 0.0205%, amr); Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Val201= (c.603C>T)?

POLG p.Val201= (c.603C>T) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Val201= (c.603C>T) in the general population?

POLG p.Val201= (c.603C>T) is ultra-rare (popmax 0.0205%, amr) (gnomAD).

How is Alpers-Huttenlocher syndrome inherited?

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

POLG p.Val201=

c.603C>T · rs768005050 · VCV195178

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0205%, amr)

Conditions

mitochondrial DNA depletion syndrome 4a

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.76 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5	GERP 1.5, phastCons 1
Overall
CADD	12.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0205% Admixed American · 10/48,796 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00841%

Overall 0.000779% 12/1,540,526 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0205%	4,880
European (non-Finnish)	0.000175%	571,700

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.Val201=
Coding: c.603C>T
MANE Select: NM_002693
dbSNP: rs768005050
Type: single nucleotide variant
Location: chr15:89333152 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.53 · 36 PDB

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.Val201Gly 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
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-val201 (accessed [today's date]).

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