# NM_032360.4(ACBD6):c.605G>A (p.Arg202Gln)

https://sugi.bio/variant/acbd6-p-arg202gln

## Summary

**ACBD6 p.Arg202Gln (c.605G>A)** is classified **Uncertain significance** in ACBD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: ambiguous (0.5328); Ultra-rare (popmax 0.0267%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense ambiguous · ultra-rare (popmax 0.0267%, amr)

## For patients & families {#patients}

This is a change in the ACBD6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [ACBD6](https://sugi.bio/atlas/gene/ACBD6/) |
| Protein change (HGVS p.) | p.Arg202Gln |
| Coding change (HGVS c.) | c.605G>A |
| MANE Select transcript | [NM_032360](https://www.ncbi.nlm.nih.gov/nuccore/NM_032360) |
| Variant type | single nucleotide variant |
| Location | chr1:180397574-180397574 (GRCh38) |
| ClinVar | [VCV4828594](https://www.ncbi.nlm.nih.gov/clinvar/variation/4828594/) |

**All HGVS expressions:** `NC_000001.10:g.180366709C>T`, `NC_000001.11:g.180397574C>T`, `NM_032360.4:c.605G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.5328) — no call either way
- REVEL 0.535 (indeterminate)
- SaProt LLR -9.329 (tolerated)
- Conservation: phyloP 7.662, GERP 1.62, phastCons 1 — highly conserved
- CADD: **PHRED 28.5**. 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 1.01** across the covering region of the MANE Select transcript (180,288,366–180,502,266), spanning 213,900 bp. Chi-square p 0.89. 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, Δ0.26 acceptor 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 **0.0267%** (amr) · FAF95 0.0166% · FAF99 0.0136% · 16/59,996 in the highest group · 39/1,613,920 alleles overall — ultra-rare (popmax 0.0267%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0267% | 3,750 |
| African / African-American | 0.0213% | 4,687 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,253 |
| East Asian | 0.00223% | 44,870 |
| European (non-Finnish) | 0.000339% | 294,984 |

*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}

**ACBD6** population constraint: LOEUF 1.037, pLI 1.2278e-05, missense-Z 0.15707. *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 **202** lies in a UniProt-annotated variant site (in nedpm; pathogenic); a UniProt-annotated variant site (in nedpm; likely pathogenic).

AlphaFold model confidence (whole protein): pLDDT 77.80, 43% of residues very-high.

**1 experimental structure(s)** (PDB): [2COP](https://www.rcsb.org/structure/2COP).

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

*Describes the biological roles of ACBD6 (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:** ACBD6's established molecular role includes fatty-acyl-CoA binding.


### Pathways affected {#pathways}

ACBD6 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:** fatty-acyl-CoA binding, lipid binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-22.

**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 | 2025-12-22 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related ACBD6 variant pages (same residue, condition, or type): [LHX4 p.Ala354Val](/variant/lhx4-p-ala354val), [LHX4 p.Arg161Gln](/variant/lhx4-p-arg161gln), [LHX4 p.Gly283Arg](/variant/lhx4-p-gly283arg), [LHX4 p.His387Gln](/variant/lhx4-p-his387gln), [LHX4 p.Leu338Trp](/variant/lhx4-p-leu338trp), [LHX4 p.Met286Thr](/variant/lhx4-p-met286thr), [LHX4 p.Ser230Asn](/variant/lhx4-p-ser230asn), [LHX4 p.Ser318Leu](/variant/lhx4-p-ser318leu).

### 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 4828594). 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.*