# NM_000026.4(ADSL):c.1355G>C (p.Arg452Pro)

https://sugi.bio/variant/adsl-p-arg452pro

## Summary

**ADSL p.Arg452Pro (c.1355G>C)** is classified **Likely pathogenic** in ADSL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-03). AlphaMissense: likely pathogenic (0.9795); Absent from gnomAD v4.1; Associated with adenylosuccinate lyase deficiency.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs775671027 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ADSL gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to adenylosuccinate lyase deficiency.

*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) | Childhood, Infancy, Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ADSL is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Adenylosuccinate lyase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Thin upper lip vermilion — Very frequent (99-80%)
- Brachycephaly — Very frequent (99-80%)
- Microcephaly — Very frequent (99-80%)
- Smooth philtrum — Very frequent (99-80%)
- Long philtrum — Very frequent (99-80%)
- Low-set ears — Very frequent (99-80%)
- Anteverted nares — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000550/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ADSL](https://sugi.bio/atlas/gene/ADSL/) |
| Protein change (HGVS p.) | p.Arg452Pro |
| Coding change (HGVS c.) | c.1355G>C |
| MANE Select transcript | [NM_000026](https://www.ncbi.nlm.nih.gov/nuccore/NM_000026) |
| dbSNP | [rs775671027](https://www.ncbi.nlm.nih.gov/snp/rs775671027/) |
| Variant type | single nucleotide variant |
| Location | chr22:40365043-40365043 (GRCh38) |
| ClinVar | [VCV1502354](https://www.ncbi.nlm.nih.gov/clinvar/variation/1502354/) |

**All HGVS expressions:** `NC_000022.10:g.40761047G>C`, `NC_000022.11:g.40365043G>C`, `NG_007993.2:g.23544G>C`, `NM_000026.4:c.1355G>C`, `NM_001123378.3:c.1191+678G>C`, `NM_001317923.2:c.1163G>C`, `NM_001363840.3:c.1355G>C`, `NR_134256.2:n.1445G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9795) — concordant with the pathogenic call
- REVEL 0.944 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.327 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 8.622, GERP 2.49, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.7**. 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 0.79** across the covering region of the MANE Select transcript (40,346,632–40,366,519), spanning 19,887 bp. Chi-square p 5.6e-07. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**ADSL** population constraint: LOEUF 0.915, pLI 2.8047e-10, missense-Z 1.7937; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **adenylosuccinate lyase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **452** lies in a UniProt-annotated variant site (in adsld; severe).

AlphaFold model confidence (whole protein): pLDDT 96.82, 95% of residues very-high.

**4 experimental structure(s)** (PDB): [2J91](https://www.rcsb.org/structure/2J91), [2VD6](https://www.rcsb.org/structure/2VD6), [4FFX](https://www.rcsb.org/structure/4FFX), [4FLC](https://www.rcsb.org/structure/4FLC).

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

*Describes the biological roles of ADSL (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:** ADSL's established molecular role includes N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Purine ribonucleoside monophosphate biosynthesis](https://reactome.org/content/detail/R-HSA-73817) | curated |

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

**Molecular function:** N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity, identical protein binding, (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido) succinate lyase (fumarate-forming) activity.

**Biological process:** AMP biosynthetic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-03.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-02-03 |

## Associated conditions {#conditions}

[adenylosuccinate lyase deficiency](https://sugi.bio/atlas/disease/adenylosuccinate-lyase-deficiency/).

**Reported phenotype names (ClinVar):** Adenylosuccinate lyase deficiency, ADSL DEFICIENCY.

## Similar variants {#similar}

Related ADSL variant pages (same residue, condition, or type): [ADSL p.Arg452His](/variant/adsl-p-arg452his), [ADSL p.Arg452Cys](/variant/adsl-p-arg452cys), [ADSL p.Arg452Gly](/variant/adsl-p-arg452gly), [ADSL c.1191+5G>C](/variant/adsl-c-1191-plus-5g-c), [ADSL c.402+1G>T](/variant/adsl-c-402-plus-1g-t), [ADSL c.482+1G>C](/variant/adsl-c-482-plus-1g-c), [ADSL c.-49T>C](/variant/adsl-c-minus-49t-c), [ADSL p.Arg141Trp](/variant/adsl-p-arg141trp).

### 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 1502354). 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.*