# NM_001610.4(ACP2):c.1067G>A (p.Arg356His)

https://sugi.bio/variant/acp2-p-arg356his

## Summary

**ACP2 p.Arg356His (c.1067G>A)** is classified **Likely benign** in ACP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-29). AlphaMissense: likely benign (0.0662); Ultra-rare (popmax 0.0329%, mid).

**At a glance:** Likely benign · review: Single submitter · rsID rs372169625 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0329%, mid)

## For patients & families {#patients}

This is a change in the ACP2 gene that is classified as likely benign — not considered disease-causing, 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 | [ACP2](https://sugi.bio/atlas/gene/ACP2/) |
| Protein change (HGVS p.) | p.Arg356His |
| Coding change (HGVS c.) | c.1067G>A |
| MANE Select transcript | [NM_001610](https://www.ncbi.nlm.nih.gov/nuccore/NM_001610) |
| dbSNP | [rs372169625](https://www.ncbi.nlm.nih.gov/snp/rs372169625/) |
| Variant type | single nucleotide variant |
| Location | chr11:47242794-47242794 (GRCh38) |
| ClinVar | [VCV2280857](https://www.ncbi.nlm.nih.gov/clinvar/variation/2280857/) |

**All HGVS expressions:** `NC_000011.10:g.47242794C>T`, `NC_000011.9:g.47264345C>T`, `NG_023296.1:g.11113G>A`, `NG_023296.2:g.11020G>A`, `NM_001302489.2:c.983G>A`, `NM_001302490.2:c.971G>A`, `NM_001302491.2:c.878G>A`, `NM_001302492.2:c.506G>A`, `NM_001357016.2:c.1067G>A`, `NM_001610.4:c.1067G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0662)
- REVEL 0.024 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.761 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -3.125, GERP -4.34 — fast-evolving / accelerated position
- CADD: **PHRED 15.31**. 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 0.87** across the covering region of the MANE Select transcript (47,240,119–47,248,789), spanning 8,670 bp. Chi-square p 0.0021. 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, Δ0.58 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 **0.0329%** (mid) · FAF95 0.0058% · FAF99 0.00312% · 2/6,080 in the highest group · 48/1,614,012 alleles overall — ultra-rare (popmax 0.0329%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0329% | 3,040 |
| South Asian | 0.00878% | 11,385 |
| East Asian | 0.00668% | 14,960 |
| African / African-American | 0.00667% | 14,987 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,829 |
| Admixed American | 0.00333% | 30,004 |
| European (non-Finnish) | 0.00212% | 47,200 |

*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}

**ACP2** population constraint: LOEUF 0.804, pLI 1.017e-06, missense-Z 1.3402. *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 **356** lies in a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 92.09, 85% of residues very-high.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-29.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-03-29 |

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

## Similar variants {#similar}

Related ACP2 variant pages (same residue, condition, or type): [ACP2 p.Arg356Cys](/variant/acp2-p-arg356cys), [ACP2 c.856-4G>A](/variant/acp2-c-856-minus-4g-a), [ACP2 p.Arg10Trp](/variant/acp2-p-arg10trp), [ACP2 p.Phe393Leu](/variant/acp2-p-phe393leu), [ACP2 p.Val416=](/variant/acp2-p-val416), [ACP2 p.Ala11Glu](/variant/acp2-p-ala11glu), [ACP2 p.Ala272Val](/variant/acp2-p-ala272val), [ACP2 p.Ala336Thr](/variant/acp2-p-ala336thr).

### 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 2280857). 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.*