# NM_003659.4(AGPS):c.870G>A (p.Gln290=)

https://sugi.bio/variant/agps-p-gln290

## Summary

**AGPS p.Gln290= (c.870G>A)** is classified **Uncertain significance** in AGPS (ClinVar, Single submitter, 2 submitters; last evaluated 2020-02-14). Very rare (popmax 0.00952%, afr); Associated with rhizomelic chondrodysplasia punctata.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs534985206 · 2 submitters · 1 linked condition · very rare (popmax 0.00952%, afr)

## For patients & families {#patients}

This is a change in the AGPS gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to rhizomelic chondrodysplasia punctata.

*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, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | AGPS is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Rhizomelic chondrodysplasia punctata** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the dentition — Very frequent (99-80%)
- Microcephaly — Very frequent (99-80%)
- Epicanthus — Very frequent (99-80%)
- Cataract — Very frequent (99-80%)
- Abnormal metaphysis morphology — Very frequent (99-80%)
- Dry skin — Very frequent (99-80%)
- Growth delay — Very frequent (99-80%)
- Sparse body hair — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013160/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AGPS](https://sugi.bio/atlas/gene/AGPS/) |
| Protein change (HGVS p.) | p.Gln290= |
| Coding change (HGVS c.) | c.870G>A |
| MANE Select transcript | [NM_003659](https://www.ncbi.nlm.nih.gov/nuccore/NM_003659) |
| dbSNP | [rs534985206](https://www.ncbi.nlm.nih.gov/snp/rs534985206/) |
| Variant type | single nucleotide variant |
| Location | chr2:177445626-177445626 (GRCh38) |
| ClinVar | [VCV991247](https://www.ncbi.nlm.nih.gov/clinvar/variation/991247/) |

**All HGVS expressions:** `NC_000002.11:g.178310354G>A`, `NC_000002.12:g.177445626G>A`, `NG_008968.1:g.57884G>A`, `NM_003659.4:c.870G>A`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 8.68, GERP 1.5, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 20.4**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.23 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00952%** (afr) · FAF95 0.00445% · FAF99 0.00314% · 7/73,496 in the highest group · 9/1,581,334 alleles overall — very rare (popmax 0.00952%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00952% | 10,499 |
| East Asian | 0.00226% | 44,338 |
| Remaining individuals (not grpmax-eligible) | 0.00164% | 61,044 |

*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}

**AGPS** population constraint: LOEUF 0.408, pLI 0.99977, missense-Z 2.8043. *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):

- **alkylglycerone-phosphate synthase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **290** lies in the fad-binding pcmh-type domain.

AlphaFold model confidence (whole protein): pLDDT 89.27, 82% of residues very-high.

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

*Describes the biological roles of AGPS (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:** AGPS's established molecular role includes alkylglycerone-phosphate synthase activity. p.Gln290= falls in the fad-binding pcmh-type domain.


### Pathways affected {#pathways}

AGPS participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Plasmalogen biosynthesis](https://reactome.org/content/detail/R-HSA-75896) | curated |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | electronic |
| [TYSND1 cleaves peroxisomal proteins](https://reactome.org/content/detail/R-HSA-9033500) | electronic |

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

**Molecular function:** alkylglycerone-phosphate synthase activity.

**Biological process:** lipid biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-02-14.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2020); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-08-31 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-02-14 |

## Associated conditions {#conditions}

[rhizomelic chondrodysplasia punctata](https://sugi.bio/atlas/disease/rhizomelic-chondrodysplasia-punctata/).

**Reported phenotype names (ClinVar):** Rhizomelic chondrodysplasia punctata, not provided, none provided.

## Similar variants {#similar}

Related AGPS variant pages (same residue, condition, or type): [AGPS p.Thr309Ile](/variant/agps-p-thr309ile), [AGPS c.261-5A>C](/variant/agps-c-261-minus-5a-c), [AGPS p.Ala69=](/variant/agps-p-ala69), [AGPS p.His362=](/variant/agps-p-his362), [AGPS p.Pro415=](/variant/agps-p-pro415), [AGPS p.Pro49=](/variant/agps-p-pro49), [AGPS p.Ala5Val](/variant/agps-p-ala5val), [AGPS p.Arg50Trp](/variant/agps-p-arg50trp).

### 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 991247). 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.*