# NM_001042573.3(ENGASE):c.1938C>G (p.Ser646Arg)

https://sugi.bio/variant/engase-p-ser646arg

## Summary

**ENGASE p.Ser646Arg (c.1938C>G)** is classified **Uncertain significance** in ENGASE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.8951); Very rare (popmax 0.00133%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the ENGASE gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [ENGASE](https://sugi.bio/atlas/gene/ENGASE/) |
| Protein change (HGVS p.) | p.Ser646Arg |
| Coding change (HGVS c.) | c.1938C>G |
| MANE Select transcript | [NM_001042573](https://www.ncbi.nlm.nih.gov/nuccore/NM_001042573) |
| Variant type | single nucleotide variant |
| Location | chr17:79086055-79086055 (GRCh38) |
| ClinVar | [VCV4664302](https://www.ncbi.nlm.nih.gov/clinvar/variation/4664302/) |

**All HGVS expressions:** `NC_000017.10:g.77082137C>G`, `NC_000017.11:g.79086055C>G`, `NM_001042573.3:c.1938C>G`, `NM_001396052.1:c.2136C>G`, `NM_001396053.1:c.2133C>G`, `NM_001396054.1:c.2127C>G`, `NM_001396055.1:c.1935C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8951)
- REVEL 0.125 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -10.519 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- SpliceAI predicts **donor gain** (Δ 0.37) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.901, GERP 1.75, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in ENGASE (of 4,298 modeled).
- CADD: **PHRED 24.7**. 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.*
- Regional missense constraint: **o/e 0.95** across the covering region of the MANE Select transcript (79,074,945–79,086,346), spanning 11,401 bp. Chi-square p 0.15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.37**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.37**.
- Pangolin: Δ**0.53** (gain), gain 0.53 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00133%** (afr) · 1/74,964 in the highest group · 1/152,274 alleles overall — very rare (popmax 0.00133%, afr).

*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}

**ENGASE** population constraint: LOEUF 1.018, pLI 2.6141e-19, missense-Z 0.63261. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.41, 71% of residues very-high.

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

*Describes the biological roles of ENGASE (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:** ENGASE's established molecular role includes mannosyl-glycoprotein endo-beta-N-acetylglucosaminidase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [N-glycan trimming in the ER and Calnexin/Calreticulin cycle](https://reactome.org/content/detail/R-HSA-532668) | curated |

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

**Molecular function:** mannosyl-glycoprotein endo-beta-N-acetylglucosaminidase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-11.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-11 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ENGASE variant pages (same residue, condition, or type): [ENGASE p.Arg555His](/variant/engase-p-arg555his), [ENGASE c.873-1G>A](/variant/engase-c-873-minus-1g-a), [ENGASE p.Ala107Val](/variant/engase-p-ala107val), [ENGASE p.Ala217Asp](/variant/engase-p-ala217asp), [ENGASE p.Ala244Val](/variant/engase-p-ala244val), [ENGASE p.Ala24Gly](/variant/engase-p-ala24gly), [ENGASE p.Ala420Val](/variant/engase-p-ala420val), [ENGASE p.Ala692Thr](/variant/engase-p-ala692thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 4664302). 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.*