# NM_024740.2(ALG9):c.694G>C (p.Ala232Pro)

https://sugi.bio/variant/alg9-p-ala232pro

## Summary

**ALG9 p.Ala232Pro (c.694G>C)** is classified **Conflicting classifications of pathogenicity** in ALG9 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2024-03-06). AlphaMissense: likely pathogenic (0.8071); Ultra-rare (popmax 0.099%, mid); Associated with ALG9-congenital disorder of glycosylation.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs36111204 · 8 submitters · 3 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.099%, mid)

## For patients & families {#patients}

This is a change in the ALG9 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 8 submitters, and is linked to ALG9-congenital disorder of glycosylation.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Infancy, Neonatal |
| Diagnostic panels | ALG9 is a diagnostic-grade gene on 16 Genomics England panels |

**Commonly reported features of ALG9-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intellectual disability — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Progressive microcephaly — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)
- Abnormal heart morphology — Frequent (79-30%)
- Pericardial effusion — Frequent (79-30%)
- Hepatomegaly — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009839/index) · [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.Ala232Pro |
| Coding change (HGVS c.) | c.694G>C |
| MANE Select transcript | [NM_024740](https://www.ncbi.nlm.nih.gov/nuccore/NM_024740) |
| dbSNP | [rs36111204](https://www.ncbi.nlm.nih.gov/snp/rs36111204/) |
| Variant type | single nucleotide variant |
| Location | chr11:111857609-111857609 (GRCh38) |
| ClinVar | [VCV96135](https://www.ncbi.nlm.nih.gov/clinvar/variation/96135/) |

**All HGVS expressions:** `NC_000011.10:g.111857609C>G`, `NC_000011.9:g.111728332C>G`, `NG_009210.1:g.18973G>C`, `NM_001077690.1:c.694G>C`, `NM_001077691.2:c.181G>C`, `NM_001077692.2:c.181G>C`, `NM_001352409.1:c.181G>C`, `NM_001352410.1:c.181G>C`, `NM_001352411.2:c.181G>C`, `NM_001352412.2:c.181G>C`, `NM_001352413.1:c.181G>C`, `NM_001352414.2:c.181G>C`, `NM_001352415.1:c.181G>C`, `NM_001352416.1:c.181G>C`, `NM_001352417.1:c.694G>C`, `NM_001352418.1:c.694G>C`, `NM_001352419.1:c.181G>C`, `NM_001352420.2:c.181G>C`, `NM_001352421.2:c.181G>C`, `NM_001352422.2:c.106G>C`, `NM_001352423.2:c.181G>C`, `NM_024740.2:c.694G>C`, `NR_147984.2:n.1090G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8071)
- REVEL 0.395 (indeterminate)
- SaProt LLR -15.246 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 7.671, GERP 1.8, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.4**. 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 0.88** across the covering region of the MANE Select transcript (111,844,656–111,871,482), spanning 26,826 bp. Chi-square p 0.019. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.099%** (mid) · FAF95 0.0528% · FAF99 0.0514% · 6/6,062 in the highest group · 718/1,614,126 alleles overall — ultra-rare (popmax 0.099%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.099% | 1,010 |
| European (non-Finnish) | 0.0564% | 1,774 |
| Finnish (not grpmax-eligible) | 0.0359% | 2,784 |
| Remaining individuals (not grpmax-eligible) | 0.0192% | 5,208 |
| Admixed American | 0.00667% | 15,002 |
| African / African-American | 0.00533% | 18,760 |
| South Asian | 0.00439% | 22,772 |

*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}

Residue **232** lies in a UniProt-annotated variant site (in).

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-03-06.

**Submitter consensus:** conflicting (6 Uncertain significance, 1 Benign, 1 Likely benign).

**Submission history:** 8 submissions (2013–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Stefan Somlo Laboratory, Yale School of Medicine | Benign | no assertion criteria provided | research | 2019-05-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-20 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-06 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-10-31 |
| Athena Diagnostics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-11-05 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-01-11 |
| Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Likely benign | criteria provided, single submitter | clinical testing | 2019-12-25 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2013-07-31 |

## Associated conditions {#conditions}

[ALG9-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/alg9-congenital-disorder-of-glycosylation/), [autosomal dominant polycystic liver disease](https://sugi.bio/atlas/disease/autosomal-dominant-polycystic-liver-disease/), [Gillessen-Kaesbach-Nishimura syndrome](https://sugi.bio/atlas/disease/gillessen-kaesbach-nishimura-syndrome/).

**Reported phenotype names (ClinVar):** ALG9 congenital disorder of glycosylation, not provided, Gillessen-Kaesbach-Nishimura syndrome, Autosomal dominant polycystic liver disease, See cases, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Il, ALG9-CDG, CDG Il, Congenital cystic disease of liver, Polycystic liver disease.

## Similar variants {#similar}

Related ALG9 variant pages (same residue, condition, or type): [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), [ALG9 c.*1722C>T](/variant/alg9-c-star-1722c-t).

### 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 96135). 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.*