# NM_024740.2(ALG9):c.1820G>A (p.Arg607Gln)

https://sugi.bio/variant/alg9-p-arg607gln

## Summary

**ALG9 p.Arg607Gln (c.1820G>A)** is classified **Uncertain significance** in ALG9 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-16). AlphaMissense: likely benign (0.1076); Very rare (popmax 0.00203%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs373830702 · 3 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00203%, nfe)

## For patients & families {#patients}

This is a change in the ALG9 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to Inborn genetic diseases.

*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 | [ALG9](https://sugi.bio/atlas/gene/ALG9/) |
| Protein change (HGVS p.) | p.Arg607Gln |
| Coding change (HGVS c.) | c.1820G>A |
| MANE Select transcript | [NM_024740](https://www.ncbi.nlm.nih.gov/nuccore/NM_024740) |
| dbSNP | [rs373830702](https://www.ncbi.nlm.nih.gov/snp/rs373830702/) |
| Variant type | single nucleotide variant |
| Location | chr11:111786434-111786434 (GRCh38) |
| ClinVar | [VCV2140708](https://www.ncbi.nlm.nih.gov/clinvar/variation/2140708/) |

**All HGVS expressions:** `NC_000011.10:g.111786434C>T`, `NC_000011.9:g.111657158C>T`, `NG_009210.2:g.90147G>A`, `NM_001077690.1:c.1799G>A`, `NM_001077691.2:c.1307G>A`, `NM_001077692.2:c.1286G>A`, `NM_001352409.1:c.1286G>A`, `NM_001352410.1:c.1286G>A`, `NM_001352411.2:c.1286G>A`, `NM_001352412.2:c.1286G>A`, `NM_001352413.1:c.1307G>A`, `NM_001352414.2:c.1307G>A`, `NM_001352415.1:c.1286G>A`, `NM_001352416.1:c.1286G>A`, `NM_001352417.1:c.1799G>A`, `NM_001352418.1:c.1676G>A`, `NM_001352419.1:c.1307G>A`, `NM_001352420.2:c.*92G>A`, `NM_001352421.2:c.*86G>A`, `NM_001352422.2:c.1211G>A`, `NM_001352423.2:c.1163G>A`, `NM_024740.2:c.1820G>A`, `NR_147984.2:n.2438G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1076)
- REVEL 0.553 (indeterminate)
- SaProt LLR -8.952 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **donor gain** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.016, GERP 0.085, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R600Q** vs ClinVar **R607Q**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 24.8**. 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 0.87** across the covering region of the MANE Select transcript (111,786,400–111,840,729), spanning 54,329 bp. Chi-square p 0.028. 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 **0.06**, acceptor gain **0.00**, donor gain **0.20**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.20**.
- Pangolin: Δ**0.21** (gain), gain 0.21 / 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 **0.00203%** (nfe) · FAF95 0.00138% · FAF99 0.00116% · 24/1,179,986 in the highest group · 27/1,613,826 alleles overall — very rare (popmax 0.00203%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,825 |
| European (non-Finnish) (grpmax) | 0.00203% | 49,166 |

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}

**ALG9** population constraint: LOEUF 0.853, pLI 1.3976e-12, missense-Z 1.7414. *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):

- **ALG9-associated autosomal dominant polycystic kidney disease** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.35, 77% of residues very-high.

**2 experimental structure(s)** (PDB): [9S6S](https://www.rcsb.org/structure/9S6S), [9S6U](https://www.rcsb.org/structure/9S6U).

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

*Describes the biological roles of ALG9 (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:** ALG9's established molecular role includes dol-P-Man:Man(8)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity. In Reactome, ALG9 is annotated in disease pathway(s) including **Defective ALG9 causes CDG-1l**.

**Disease mechanism (Reactome):** ALG9 loss or alteration is curated in [Defective ALG9 causes CDG-1l](https://reactome.org/content/detail/R-HSA-4720454).

### Pathways affected {#pathways}

ALG9 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ALG9 causes CDG-1l](https://reactome.org/content/detail/R-HSA-4720454) | curated |
| [Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein](https://reactome.org/content/detail/R-HSA-446193) | curated |

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

**Molecular function:** dol-P-Man:Man(8)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity, dol-P-Man:Man(6)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity.

**Biological process:** protein N-linked glycosylation, dolichol-linked oligosaccharide biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-01-16.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-19 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-03 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-16 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [Gillessen-Kaesbach-Nishimura syndrome](https://sugi.bio/atlas/disease/gillessen-kaesbach-nishimura-syndrome/), [ALG9-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/alg9-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, ALG9 congenital disorder of glycosylation, Gillessen-Kaesbach-Nishimura syndrome, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Il, ALG9-CDG, CDG Il.

## Similar variants {#similar}

Related ALG9 variant pages (same residue, condition, or type): [ALG9 p.Arg607Trp](/variant/alg9-p-arg607trp), [ALG9 c.566-1G>A](/variant/alg9-c-566-minus-1g-a), [ALG9 c.896-2A>G](/variant/alg9-c-896-minus-2a-g), [ALG9 p.Arg143Ter](/variant/alg9-p-arg143ter), [ALG9 p.Trp248Ter](/variant/alg9-p-trp248ter), [ALG9 p.Tyr287Cys](/variant/alg9-p-tyr287cys), [ALG9 c.*1607C>T](/variant/alg9-c-star-1607c-t), [ALG9 c.*1624A>C](/variant/alg9-c-star-1624a-c).

### 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 2140708). 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.*