# NM_023928.5(AACS):c.223C>A (p.Arg75Ser)

https://sugi.bio/variant/aacs-p-arg75ser

## Summary

**AACS p.Arg75Ser (c.223C>A)** is classified **Uncertain significance** in AACS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.1821); Very rare (popmax 0.00667%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00667%, amr)

## For patients & families {#patients}

This is a change in the AACS gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [AACS](https://sugi.bio/atlas/gene/AACS/) |
| Protein change (HGVS p.) | p.Arg75Ser |
| Coding change (HGVS c.) | c.223C>A |
| MANE Select transcript | [NM_023928](https://www.ncbi.nlm.nih.gov/nuccore/NM_023928) |
| Variant type | single nucleotide variant |
| Location | chr12:125073965-125073965 (GRCh38) |
| ClinVar | [VCV4148836](https://www.ncbi.nlm.nih.gov/clinvar/variation/4148836/) |

**All HGVS expressions:** `NC_000012.11:g.125558511C>A`, `NC_000012.12:g.125073965C>A`, `NM_001319839.2:c.223C>A`, `NM_001319840.2:c.223C>A`, `NM_001414675.1:c.223C>A`, `NM_001414676.1:c.223C>A`, `NM_001414677.1:c.223C>A`, `NM_001414678.1:c.223C>A`, `NM_023928.5:c.223C>A`, `NR_183032.1:n.373C>A`, `NR_183033.1:n.373C>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** (0.1821)
- REVEL 0.033 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.525 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.516, GERP -1.61, phastCons 0.004 — weakly conserved position
- CADD: **PHRED 8.346**. 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 0.98** across the covering region of the MANE Select transcript (125,065,585–125,142,226), spanning 76,641 bp. Chi-square p 0.59. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.44 donor gain), 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 **0.00667%** (amr) · FAF95 0.00226% · FAF99 0.00135% · 4/59,958 in the highest group · 9/1,461,174 alleles overall — very rare (popmax 0.00667%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00667% | 14,989 |
| European (non-Finnish) | 0.000424% | 235,891 |

*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}

**AACS** population constraint: LOEUF 0.967, pLI 8.8541e-18, missense-Z 0.48387. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.09, 78% of residues very-high.

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

*Describes the biological roles of AACS (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.*


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of Ketone Bodies](https://reactome.org/content/detail/R-HSA-77111) | other |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-10 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related AACS variant pages (same residue, condition, or type): [AACS p.Arg75His](/variant/aacs-p-arg75his), [AACS c.1881+8C>G](/variant/aacs-c-1881-plus-8c-g), [AACS p.Arg107=](/variant/aacs-p-arg107), [AACS p.Glu564Gln](/variant/aacs-p-glu564gln), [AACS p.Ile430=](/variant/aacs-p-ile430), [AACS p.Phe276=](/variant/aacs-p-phe276), [AACS p.Ala169Thr](/variant/aacs-p-ala169thr), [AACS p.Ala271Pro](/variant/aacs-p-ala271pro).

### 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 4148836). 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.*