# NM_176787.5(PIGN):c.1494dup (p.Leu499fs)

https://sugi.bio/variant/pign-p-leu499fs

## Summary

**PIGN p.Leu499fs (c.1494dup)** is classified **Pathogenic/Likely pathogenic** in PIGN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-15). Very rare (popmax 0.00223%, eas); Associated with multiple congenital anomalies-hypotonia-seizures syndrome 1.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs750418747 · 2 submitters · 1 linked condition · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the PIGN gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to multiple congenital anomalies-hypotonia-seizures syndrome 1.

*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/0012781/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PIGN](https://sugi.bio/atlas/gene/PIGN/) |
| Protein change (HGVS p.) | p.Leu499fs |
| Coding change (HGVS c.) | c.1494dup |
| MANE Select transcript | [NM_176787](https://www.ncbi.nlm.nih.gov/nuccore/NM_176787) |
| dbSNP | [rs750418747](https://www.ncbi.nlm.nih.gov/snp/rs750418747/) |
| Variant type | Duplication |
| Location | chr18:62109913-62109914 (GRCh38) |
| ClinVar | [VCV658963](https://www.ncbi.nlm.nih.gov/clinvar/variation/658963/) |

**All HGVS expressions:** `NC_000018.10:g.62109919dup`, `NC_000018.9:g.59777152dup`, `NG_033144.1:g.82143dup`, `NM_012327.6:c.1494dup`, `NM_176787.4:c.1494dup`, `NM_176787.4:c.1494dupT`, `NM_176787.5:c.1494dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 6.665, GERP 2.12, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.46, pLI 1.5077e-09. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 17 of 31**, so the transcript is predicted to undergo NMD.
- 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 **0.00223%** (eas) · FAF95 0.000183% · FAF99 0.00012% · 1/44,786 in the highest group · 10/1,613,250 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,225 |
| East Asian (grpmax) | 0.00223% | 44,786 |
| South Asian | 0.0011% | 91,052 |
| European (non-Finnish) | 0.000509% | 196,575 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**PIGN** population constraint: LOEUF 1.46, pLI 1.5077e-09, missense-Z 0.29539; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/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):

- **multiple congenital anomalies-hypotonia-seizures syndrome 1** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.33, 62% of residues very-high.

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

*Describes the biological roles of PIGN (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.*


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of glycosylphosphatidylinositol (GPI)](https://reactome.org/content/detail/R-HSA-162710) | curated |

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-15.

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

**Submission history:** 2 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-07-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-15 |

## Associated conditions {#conditions}

[multiple congenital anomalies-hypotonia-seizures syndrome 1](https://sugi.bio/atlas/disease/multiple-congenital-anomalies-hypotonia-seizures-syndrome-1/).

**Reported phenotype names (ClinVar):** Multiple congenital anomalies-hypotonia-seizures syndrome 1, not provided, PIGN-CDG, Congenital disorder of glycosylation due to PIGN deficiency, GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 3, none provided.

## Similar variants {#similar}

Related PIGN variant pages (same residue, condition, or type): [PIGN p.Ala273fs](/variant/pign-p-ala273fs), [PIGN p.Gly800fs](/variant/pign-p-gly800fs), [PIGN p.Met328fs](/variant/pign-p-met328fs), [PIGN c.1116+12dup](/variant/pign-c-1116-plus-12dup), [PIGN c.2577-13dup](/variant/pign-c-2577-minus-13dup), [PIGN c.2620-17_2620-15dup](/variant/pign-c-2620-minus-17-2620-minus-15dup), [PIGN c.2620-17_2620-16dup](/variant/pign-c-2620-minus-17-2620-minus-16dup), [PIGN c.2620-17dup](/variant/pign-c-2620-minus-17dup).

### 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 658963). 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.*