# NM_024560.4(ACSS3):c.526C>T (p.Pro176Ser)

https://sugi.bio/variant/acss3-p-pro176ser

## Summary

**ACSS3 p.Pro176Ser (c.526C>T)** is classified **Uncertain significance** in ACSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: likely pathogenic (0.9068); Very rare (popmax 0.00512%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1258810302 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00512%, amr)

## For patients & families {#patients}

This is a change in the ACSS3 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 | [ACSS3](https://sugi.bio/atlas/gene/ACSS3/) |
| Protein change (HGVS p.) | p.Pro176Ser |
| Coding change (HGVS c.) | c.526C>T |
| MANE Select transcript | [NM_024560](https://www.ncbi.nlm.nih.gov/nuccore/NM_024560) |
| dbSNP | [rs1258810302](https://www.ncbi.nlm.nih.gov/snp/rs1258810302/) |
| Variant type | single nucleotide variant |
| Location | chr12:81134885-81134885 (GRCh38) |
| ClinVar | [VCV3141109](https://www.ncbi.nlm.nih.gov/clinvar/variation/3141109/) |

**All HGVS expressions:** `NC_000012.11:g.81528664C>T`, `NC_000012.12:g.81134885C>T`, `NM_001330242.2:c.523C>T`, `NM_001330243.2:c.-480C>T`, `NM_024560.4:c.526C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9068)
- REVEL 0.643 (indeterminate)
- SaProt LLR -9.594 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate
- SpliceAI predicts **acceptor gain** (Δ 0.45) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.618, GERP 2.35, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. 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 0.94** across the covering region of the MANE Select transcript (81,078,121–81,254,919), spanning 176,798 bp. Chi-square p 0.074. 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 **0.00**, acceptor gain **0.45**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.45**, donor gain **0.00**.
- Pangolin: Δ**0.29** (gain), gain 0.29 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00512%** (amr) · FAF95 0.00136% · FAF99 0.000677% · 3/58,610 in the highest group · 10/1,601,990 alleles overall — very rare (popmax 0.00512%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00512% | 19,537 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 61,992 |
| European (non-Finnish) | 0.000511% | 195,557 |

*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}

**ACSS3** population constraint: LOEUF 0.931, pLI 2.5819e-14, missense-Z 0.93209. *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 87.93, 71% of residues very-high.

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

*Describes the biological roles of ACSS3 (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:** ACSS3's established molecular role includes propionate-CoA ligase activity.


### Pathways affected {#pathways}

ACSS3 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of Ketone Bodies](https://reactome.org/content/detail/R-HSA-77111) | curated |
| [MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis](https://reactome.org/content/detail/R-HSA-9841922) | electronic |

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

**Molecular function:** propionate-CoA ligase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-01.

**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 | 2024-03-01 |

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

## Similar variants {#similar}

Related ACSS3 variant pages (same residue, condition, or type): [ACSS3 p.Ala193Thr](/variant/acss3-p-ala193thr), [ACSS3 p.Ala262Glu](/variant/acss3-p-ala262glu), [ACSS3 p.Ala317Thr](/variant/acss3-p-ala317thr), [ACSS3 p.Ala377Thr](/variant/acss3-p-ala377thr), [ACSS3 p.Ala53Glu](/variant/acss3-p-ala53glu), [ACSS3 p.Ala570Thr](/variant/acss3-p-ala570thr), [ACSS3 p.Ala657Asp](/variant/acss3-p-ala657asp), [ACSS3 p.Ala80Val](/variant/acss3-p-ala80val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3141109). 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.*