# NM_007214.5(SEC63):c.1605dup (p.Pro536fs)

https://sugi.bio/variant/sec63-p-pro536fs

## Summary

**SEC63 p.Pro536fs (c.1605dup)** is classified **Conflicting classifications of pathogenicity** in SEC63 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-29). Rare (popmax 0.135%, amr); Associated with polycystic liver disease 2.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs752868449 · 5 submitters · 1 linked condition · rare (popmax 0.135%, amr)

## For patients & families {#patients}

This is a change in the SEC63 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to polycystic liver disease 2.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016174/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SEC63](https://sugi.bio/atlas/gene/SEC63/) |
| Protein change (HGVS p.) | p.Pro536fs |
| Coding change (HGVS c.) | c.1605dup |
| MANE Select transcript | [NM_007214](https://www.ncbi.nlm.nih.gov/nuccore/NM_007214) |
| dbSNP | [rs752868449](https://www.ncbi.nlm.nih.gov/snp/rs752868449/) |
| Variant type | Duplication |
| Location | chr6:107893550-107893551 (GRCh38) |
| ClinVar | [VCV194646](https://www.ncbi.nlm.nih.gov/clinvar/variation/194646/) |

**All HGVS expressions:** `NC_000006.11:g.108214764dup`, `NC_000006.12:g.107893560dup`, `NG_008270.1:g.69728dup`, `NM_007214.5:c.1605dup`

## 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 0.348, GERP -1.14, phastCons 0.151 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.532, pLI 0.90762), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 16 of 21**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 25.0**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.135%** (amr) · FAF95 0.11% · FAF99 0.101% · 73/53,924 in the highest group · 1,040/1,485,648 alleles overall — rare (popmax 0.135%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.135% | 739 |
| Finnish (not grpmax-eligible) | 0.0813% | 1,230 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0775% | 1,290 |
| European (non-Finnish) | 0.071% | 1,409 |
| South Asian | 0.07% | 1,428 |
| Remaining individuals (not grpmax-eligible) | 0.0598% | 1,673 |
| African / African-American | 0.0327% | 3,059 |
| East Asian | 0.0241% | 4,156 |
| Middle Eastern | 0.0181% | 5,530 |

*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}

**SEC63** population constraint: LOEUF 0.532, pLI 0.90762, missense-Z 2.4462; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **polycystic liver disease 2** — Definitive (AD)

## Protein context {#protein}

Residue **536** lies in the 'disordered' region; a UniProt-annotated variant site (in pcld2); the sec63 1 domain.

AlphaFold model confidence (whole protein): pLDDT 77.71, 42% of residues very-high.

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

*Describes the biological roles of SEC63 (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:** SEC63's established molecular role includes RNA binding. p.Pro536fs falls in the disordered region.


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

**Molecular function:** RNA binding.

**Biological process:** SRP-dependent cotranslational protein targeting to membrane, post-translational protein targeting to endoplasmic reticulum membrane, post-translational protein targeting to membrane, translocation.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-29.

**Submitter consensus:** conflicting (3 Likely pathogenic, 1 Pathogenic, 1 Likely benign).

**Submission history:** 5 submissions (2014–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-07-10 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2014-07-24 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |
| Genomics And Bioinformatics Analysis Resource, Columbia University | Likely pathogenic | no assertion criteria provided | research |  |
| Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-11-29 |

## Associated conditions {#conditions}

[polycystic liver disease 2](https://sugi.bio/atlas/disease/polycystic-liver-disease-2/).

**Reported phenotype names (ClinVar):** Polycystic liver disease 2, not provided, not specified, Polycystic liver disease 2 with or without kidney cysts, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related SEC63 variant pages (same residue, condition, or type): [SEC63 p.Val398fs](/variant/sec63-p-val398fs), [SEC63 p.Met1fs](/variant/sec63-p-met1fs), [SEC63 c.1210-18dup](/variant/sec63-c-1210-minus-18dup), [SEC63 c.1936-27_1936-25dup](/variant/sec63-c-1936-minus-27-1936-minus-25dup), [SEC63 c.340-6_340-4dup](/variant/sec63-c-340-minus-6-340-minus-4dup), [SEC63 p.Arg98fs](/variant/sec63-p-arg98fs), [SEC63 p.Asn365fs](/variant/sec63-p-asn365fs), [SEC63 p.Pro443fs](/variant/sec63-p-pro443fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 194646). 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.*