# NM_013338.5(ALG5):c.236G>A (p.Arg79Gln)

https://sugi.bio/variant/alg5-p-arg79gln

## Summary

**ALG5 p.Arg79Gln (c.236G>A)** is classified **Uncertain significance** in ALG5 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-28). AlphaMissense: likely pathogenic (0.7801); Very rare (popmax 0.000424%, nfe); Associated with ALG5-related disorder.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the ALG5 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to ALG5-related disorder.

*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 | [ALG5](https://sugi.bio/atlas/gene/ALG5/) |
| Protein change (HGVS p.) | p.Arg79Gln |
| Coding change (HGVS c.) | c.236G>A |
| MANE Select transcript | [NM_013338](https://www.ncbi.nlm.nih.gov/nuccore/NM_013338) |
| Variant type | single nucleotide variant |
| Location | chr13:36995427-36995427 (GRCh38) |
| ClinVar | [VCV3346143](https://www.ncbi.nlm.nih.gov/clinvar/variation/3346143/) |

**All HGVS expressions:** `NC_000013.10:g.37569564C>T`, `NC_000013.11:g.36995427C>T`, `NM_001142364.1:c.236G>A`, `NM_013338.5:c.236G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7801)
- REVEL 0.384 (indeterminate)
- SaProt LLR -13.558 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.72) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.905, GERP 2.27, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 35.0**. 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.*
- Regional missense constraint: **o/e 0.78** across the covering region of the MANE Select transcript (36,949,945–36,999,300), spanning 49,355 bp. Chi-square p 9.9e-06. 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 **0.72**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,178,390 in the highest group · 5/1,455,372 alleles overall — very rare (popmax 0.000424%, nfe).

*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}

**ALG5** population constraint: LOEUF 0.823, pLI 0.015945, missense-Z 1.2373. *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):

- **autosomal dominant polycystic kidney disease** — Moderate (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.29, 80% of residues very-high.

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

*Describes the biological roles of ALG5 (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:** ALG5's established molecular role includes dolichyl-phosphate beta-glucosyltransferase activity.


### Pathways affected {#pathways}

ALG5 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of dolichyl-phosphate-glucose](https://reactome.org/content/detail/R-HSA-480985) | curated |

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

**Molecular function:** dolichyl-phosphate beta-glucosyltransferase activity.

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

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-04-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-04-28 |

## Associated conditions {#conditions}

[ALG5-related disorder](https://sugi.bio/atlas/disease/alg5-related-disorder/).

**Reported phenotype names (ClinVar):** ALG5-related disorder, ALG5-related condition.

## Same-residue context {#hotspot}

Residue **79** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ALG5 p.Arg79Trp](/variant/alg5-p-arg79trp). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ALG5 variant pages (same residue, condition, or type): [ALG5 p.Arg79Trp](/variant/alg5-p-arg79trp), [ALG5 p.Arg212Cys](/variant/alg5-p-arg212cys), [ALG5 p.Ala19Ser](/variant/alg5-p-ala19ser), [ALG5 p.Ala18=](/variant/alg5-p-ala18), [ALG5 p.Ala2=](/variant/alg5-p-ala2), [ALG5 p.Gly12=](/variant/alg5-p-gly12), [ALG5 p.Leu11Val](/variant/alg5-p-leu11val), [ALG5 p.Thr249=](/variant/alg5-p-thr249).

### 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 3346143). 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.*