# NM_002693.3(POLG):c.603C>T (p.Val201=)

https://sugi.bio/variant/polg-p-val201

## Summary

**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.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs768005050 · 4 submitters · 1 linked condition · ultra-rare (popmax 0.0205%, amr)

## For patients & families {#patients}

This is a change in the POLG gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to mitochondrial DNA depletion syndrome 4a.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | POLG is a diagnostic-grade gene on 34 Genomics England panels |

**Commonly reported features of Alpers-Huttenlocher syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Microcephaly — Frequent (79-30%)
- Abnormality of the eye — Frequent (79-30%)
- Abnormality of vision — Frequent (79-30%)
- Ataxia — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)
- Spasticity — Frequent (79-30%)
- Coma — Frequent (79-30%)
- Global developmental delay — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005783/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [POLG](https://sugi.bio/atlas/gene/POLG/) |
| Protein change (HGVS p.) | p.Val201= |
| Coding change (HGVS c.) | c.603C>T |
| MANE Select transcript | [NM_002693](https://www.ncbi.nlm.nih.gov/nuccore/NM_002693) |
| dbSNP | [rs768005050](https://www.ncbi.nlm.nih.gov/snp/rs768005050/) |
| Variant type | single nucleotide variant |
| Location | chr15:89333152-89333152 (GRCh38) |
| ClinVar | [VCV195178](https://www.ncbi.nlm.nih.gov/clinvar/variation/195178/) |

**All HGVS expressions:** `LRG_765:g.6644C>T`, `LRG_765t1:c.603C>T`, `NC_000015.10:g.89333152G>A`, `NC_000015.9:g.89876383G>A`, `NG_008218.2:g.6644C>T`, `NM_001126131.2:c.603C>T`, `NM_002693.3:c.603C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 5.016, GERP 1.52, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 12.36**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.76 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0205%** (amr) · FAF95 0.011% · FAF99 0.00841% · 10/48,796 in the highest group · 12/1,540,526 alleles overall — ultra-rare (popmax 0.0205%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0205% | 4,880 |
| European (non-Finnish) | 0.000175% | 571,700 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**POLG** population constraint: LOEUF 0.847, pLI 2.1691e-26, missense-Z -0.43598. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Leigh syndrome** — Limited (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.53, 44% of residues very-high.

**36 experimental structure(s)** (PDB): [3IKM](https://www.rcsb.org/structure/3IKM), [4ZTU](https://www.rcsb.org/structure/4ZTU), [4ZTZ](https://www.rcsb.org/structure/4ZTZ), [5C51](https://www.rcsb.org/structure/5C51), [5C52](https://www.rcsb.org/structure/5C52), [5C53](https://www.rcsb.org/structure/5C53) — incl. mutant structure 9GGB.

## What this gene does {#gene-function}

*Describes the biological roles of POLG (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** POLG's established molecular role includes protease binding.


### Pathways affected {#pathways}

POLG participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Strand-asynchronous mitochondrial DNA replication](https://reactome.org/content/detail/R-HSA-9913635) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protease binding, DNA binding, chromatin binding, DNA-directed DNA polymerase activity, single-stranded DNA 3'-5' DNA exonuclease activity, 3'-5' exonuclease activity.

**Biological process:** DNA-templated DNA replication, mitochondrial DNA replication, base-excision repair, base-excision repair, gap-filling, DNA replication proofreading.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-07-30.

**Submitter consensus:** conflicting (2 Likely benign, 2 Uncertain significance).

**Submission history:** 4 submissions (2015–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-30 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-01 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2017-02-09 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-03-06 |

## Associated conditions {#conditions}

[mitochondrial DNA depletion syndrome 4a](https://sugi.bio/atlas/disease/mitochondrial-dna-depletion-syndrome-4a/).

**Reported phenotype names (ClinVar):** Progressive sclerosing poliodystrophy, not specified, not provided, AllHighlyPenetrant, none provided, Alpers Syndrome, Mitochondrial DNA depletion syndrome 4A (Alpers type), Mitochondrial DNA Depletion Syndrome 4A, ALPERS PROGRESSIVE INFANTILE POLIODYSTROPHY, ALPERS DIFFUSE DEGENERATION OF CEREBRAL GRAY MATTER WITH HEPATIC CIRRHOSIS.

## Similar variants {#similar}

Related POLG variant pages (same residue, condition, or type): [POLG p.Val201Gly](/variant/polg-p-val201gly), [POLG c.3643+2T>C](/variant/polg-c-3643-plus-2t-c), [POLG p.Ala1105Pro](/variant/polg-p-ala1105pro), [POLG p.Arg1096Cys](/variant/polg-p-arg1096cys), [POLG p.Asp1184Asn](/variant/polg-p-asp1184asn), [POLG p.Gln1175Ter](/variant/polg-p-gln1175ter), [POLG p.Lys1191Asn](/variant/polg-p-lys1191asn), [POLG c.3483-14T>C](/variant/polg-c-3483-minus-14t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 195178). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*