Is POLG p.Ser216Phe (c.647C>T) pathogenic?

POLG p.Ser216Phe (c.647C>T) is classified Uncertain significance in POLG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-15). AlphaMissense: likely pathogenic (0.9576); Very rare (popmax 0.00262%, sas); Associated with mitochondrial DNA depletion syndrome 4a.

What condition is associated with POLG p.Ser216Phe (c.647C>T)?

POLG p.Ser216Phe (c.647C>T) is associated with mitochondrial DNA depletion syndrome 4a (ClinVar).

How common is POLG p.Ser216Phe (c.647C>T) in the general population?

POLG p.Ser216Phe (c.647C>T) is very rare (popmax 0.00262%, sas) (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.Ser216Phe (c.647C>T)?

AlphaMissense predicts likely pathogenic (score 0.9576) — an in-silico prediction, not a clinical call.

POLG p.Ser216Phe

c.647C>T · rs763592738 · VCV1491241

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9576 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00262%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial DNA depletion syndrome 4a

Computational evidence

Protein change
AlphaMissense	0.9576	likely pathogenic
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -15.68	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 13 kb · p 0.21 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00262% South Asian · 2/76,366 alleles

Filtering AF 0.000435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000163%

Overall 0.000395% 6/1,519,678 alleles · very rare exomes 6/1,367,330 · genomes 0/152,348 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00262%	38,183
Admixed American	0.00219%	45,698
European (non-Finnish)	0.000265%	377,956

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.Ser216Phe
Coding: c.647C>T
MANE Select: NM_002693
dbSNP: rs763592738
Type: single nucleotide variant
Location: chr15:89333108 (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.Ser216Tyr Uncertain significance ★ ⚠ same residue
POLG p.Ser216fs 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

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-ser216phe (accessed [today's date]).

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