# NM_006111.3(ACAA2):c.1115G>A (p.Arg372Gln)

https://sugi.bio/variant/acaa2-p-arg372gln

## Summary

**ACAA2 p.Arg372Gln (c.1115G>A)** is classified **Uncertain significance** in ACAA2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-02). AlphaMissense: likely benign (0.1248); Ultra-rare (popmax 0.0307%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 2 submitters · AlphaMissense likely benign · ultra-rare (popmax 0.0307%, sas)

## For patients & families {#patients}

This is a change in the ACAA2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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 | [ACAA2](https://sugi.bio/atlas/gene/ACAA2/) |
| Protein change (HGVS p.) | p.Arg372Gln |
| Coding change (HGVS c.) | c.1115G>A |
| MANE Select transcript | [NM_006111](https://www.ncbi.nlm.nih.gov/nuccore/NM_006111) |
| Variant type | single nucleotide variant |
| Location | chr18:49783926-49783926 (GRCh38) |
| ClinVar | [VCV4431765](https://www.ncbi.nlm.nih.gov/clinvar/variation/4431765/) |

**All HGVS expressions:** `NC_000018.10:g.49783926C>T`, `NC_000018.9:g.47310296C>T`, `NM_006111.2:c.1115G>A`, `NM_006111.3:c.1115G>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** (0.1248)
- REVEL 0.515 (indeterminate)
- SaProt LLR -9.815 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 0.762, phastCons 0.221 — weakly conserved position
- CADD: **PHRED 22.2**. 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 0.97** across the covering region of the MANE Select transcript (49,783,850–49,813,484), spanning 29,634 bp. Chi-square p 0.51. 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>A, Δ0.25 acceptor 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 **0.0307%** (sas) · FAF95 0.0218% · FAF99 0.0188% · 28/91,060 in the highest group · 57/1,613,848 alleles overall — ultra-rare (popmax 0.0307%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0307% | 3,252 |
| East Asian | 0.00669% | 14,952 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,620 |
| African / African-American | 0.00267% | 37,499 |
| European (non-Finnish) | 0.0017% | 58,994 |

*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}

**ACAA2** population constraint: LOEUF 1.148, pLI 1.964e-09, missense-Z 0.4051. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **372** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 97.49, 98% of residues very-high.

**2 experimental structure(s)** (PDB): [4C2J](https://www.rcsb.org/structure/4C2J), [4C2K](https://www.rcsb.org/structure/4C2K).

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

*Describes the biological roles of ACAA2 (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:** ACAA2's established molecular role includes RNA binding.


### Pathways affected {#pathways}

ACAA2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial Fatty Acid Beta-Oxidation](https://reactome.org/content/detail/R-HSA-77289) | curated |

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

**Molecular function:** RNA binding, acetyl-CoA C-acetyltransferase activity, acetyl-CoA C-acyltransferase activity, fatty acyl-CoA hydrolase activity.

**Biological process:** cellular response to hypoxia, negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway, negative regulation of mitochondrial membrane permeability involved in apoptotic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-02.

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

**Submission history:** 2 submissions (2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-02 |

**Reported phenotype names (ClinVar):** Thyroid cancer, nonmedullary, 1, not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ACAA2 variant pages (same residue, condition, or type): [ACAA2 p.Arg372Leu](/variant/acaa2-p-arg372leu), [ACAA2 p.Tyr198Asn](/variant/acaa2-p-tyr198asn), [ACAA2 p.Ala183Thr](/variant/acaa2-p-ala183thr), [ACAA2 p.Ala196Thr](/variant/acaa2-p-ala196thr), [ACAA2 p.Ala250Thr](/variant/acaa2-p-ala250thr), [ACAA2 p.Ala267Gly](/variant/acaa2-p-ala267gly), [ACAA2 p.Ala70Ser](/variant/acaa2-p-ala70ser), [ACAA2 p.Arg133His](/variant/acaa2-p-arg133his).

### 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 4431765). 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.*