# NM_013247.5(HTRA2):c.1056C>T (p.Ser352=)

https://sugi.bio/variant/htra2-p-ser352

## Summary

**HTRA2 p.Ser352= (c.1056C>T)** is classified **Conflicting classifications of pathogenicity** in HTRA2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-08). Ultra-rare (popmax 0.01%, amr); Associated with Parkinson disease 13, autosomal dominant, susceptibility to.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs781540048 · 4 submitters · 1 linked condition · ultra-rare (popmax 0.01%, amr)

## For patients & families {#patients}

This is a change in the HTRA2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to Parkinson disease 13, autosomal dominant, susceptibility to.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HTRA2](https://sugi.bio/atlas/gene/HTRA2/) |
| Protein change (HGVS p.) | p.Ser352= |
| Coding change (HGVS c.) | c.1056C>T |
| MANE Select transcript | [NM_013247](https://www.ncbi.nlm.nih.gov/nuccore/NM_013247) |
| dbSNP | [rs781540048](https://www.ncbi.nlm.nih.gov/snp/rs781540048/) |
| Variant type | single nucleotide variant |
| Location | chr2:74531866-74531866 (GRCh38) |
| ClinVar | [VCV895799](https://www.ncbi.nlm.nih.gov/clinvar/variation/895799/) |

**All HGVS expressions:** `NC_000002.11:g.74758993C>T`, `NC_000002.12:g.74531866C>T`, `NG_012163.1:g.7462C>T`, `NG_033037.1:g.2982G>A`, `NG_033047.1:g.27070G>A`, `NM_001321727.1:c.1086C>T`, `NM_001321728.1:c.1056C>T`, `NM_013247.5:c.1056C>T`, `NM_145074.2:c.861C>T`, `NR_135769.1:n.1698C>T`, `NR_135770.1:n.1126C>T`, `NR_135771.1:n.1110C>T`, `NR_135772.1:n.1130C>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 1.91, GERP -1.63, phastCons 1 — weakly conserved position
- CADD: **PHRED 9.224**. 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 (C>A, Δ0.52 acceptor 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 **0.01%** (amr) · FAF95 0.00782% · FAF99 0.00727% · 6/59,996 in the highest group · 125/1,613,846 alleles overall — ultra-rare (popmax 0.01%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.01% | 9,999 |
| European (non-Finnish) | 0.00924% | 10,826 |
| South Asian | 0.00659% | 15,177 |
| African / African-American | 0.00267% | 37,441 |
| East Asian | 0.00223% | 44,892 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,468 |

*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}

**HTRA2** population constraint: LOEUF 0.778, pLI 0.00020521, missense-Z 2.3681. *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):

- **3-methylglutaconic aciduria type 8** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 74.83, 51% of residues very-high.

**13 experimental structure(s)** (PDB): [1LCY](https://www.rcsb.org/structure/1LCY), [2PZD](https://www.rcsb.org/structure/2PZD), [5FHT](https://www.rcsb.org/structure/5FHT), [5M3N](https://www.rcsb.org/structure/5M3N), [5M3O](https://www.rcsb.org/structure/5M3O), [5TNY](https://www.rcsb.org/structure/5TNY) — incl. mutant structure 5FHT.

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

*Describes the biological roles of HTRA2 (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:** HTRA2's established molecular role includes serine-type endopeptidase activity.


### Pathways affected {#pathways}

HTRA2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |
| [Mitochondrial unfolded protein response (UPRmt)](https://reactome.org/content/detail/R-HSA-9841251) | curated |

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

**Molecular function:** serine-type endopeptidase activity, peptidase activity, serine-type peptidase activity, protein serine/threonine kinase inhibitor activity, identical protein binding, ubiquitin ligase inhibitor activity.

**Biological process:** proteolysis, mitochondrion organization, intrinsic apoptotic signaling pathway in response to DNA damage, protein catabolic process, cellular response to oxidative stress, cellular response to heat.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-10-08.

**Submitter consensus:** conflicting (3 Likely benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-02-12 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-11-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-08 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-05-03 |

## Associated conditions {#conditions}

[Parkinson disease 13, autosomal dominant, susceptibility to](https://sugi.bio/atlas/disease/parkinson-disease-13-autosomal-dominant-susceptibility-to/).

**Reported phenotype names (ClinVar):** Parkinson disease 13, autosomal dominant, susceptibility to, not provided, not specified, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related HTRA2 variant pages (same residue, condition, or type): [HTRA2 p.Ser352Cys](/variant/htra2-p-ser352cys), [AUP1 p.Pro9Ser](/variant/aup1-p-pro9ser), [HTRA2 c.507-10T>A](/variant/htra2-c-507-minus-10t-a), [HTRA2 c.507-9C>A](/variant/htra2-c-507-minus-9c-a), [HTRA2 p.Arg432Ter](/variant/htra2-p-arg432ter), [HTRA2 p.Gly26Glu](/variant/htra2-p-gly26glu), [HTRA2 p.Thr449Ile](/variant/htra2-p-thr449ile), [HTRA2 c.1046-5C>G](/variant/htra2-c-1046-minus-5c-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 895799). 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.*