# NM_001363941.2(ARMC8):c.482G>A (p.Arg161His)

https://sugi.bio/variant/armc8-p-arg161his

## Summary

**ARMC8 p.Arg161His (c.482G>A)** is classified **Uncertain significance** in ARMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-21). AlphaMissense: likely benign (0.0869); Very rare (popmax 0.00161%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs200413853 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00161%, nfe)

## For patients & families {#patients}

This is a change in the ARMC8 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 | [ARMC8](https://sugi.bio/atlas/gene/ARMC8/) |
| Protein change (HGVS p.) | p.Arg161His |
| Coding change (HGVS c.) | c.482G>A |
| MANE Select transcript | [NM_001363941](https://www.ncbi.nlm.nih.gov/nuccore/NM_001363941) |
| dbSNP | [rs200413853](https://www.ncbi.nlm.nih.gov/snp/rs200413853/) |
| Variant type | single nucleotide variant |
| Location | chr3:138228964-138228964 (GRCh38) |
| ClinVar | [VCV2604768](https://www.ncbi.nlm.nih.gov/clinvar/variation/2604768/) |

**All HGVS expressions:** `NC_000003.11:g.137947806G>A`, `NC_000003.12:g.138228964G>A`, `NM_001267041.2:c.435+5231G>A`, `NM_001267042.3:c.482G>A`, `NM_001282342.2:c.309+5231G>A`, `NM_001363941.2:c.482G>A`, `NM_001363942.1:c.356G>A`, `NM_014154.4:c.440G>A`, `NM_015396.6:c.440G>A`, `NM_213654.3:c.440G>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** (0.0869)
- REVEL 0.06 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -3.644 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 11.85, GERP 2.48, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.0**. 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 0.87** across the covering region of the MANE Select transcript (138,187,555–138,241,927), spanning 54,372 bp. Chi-square p 0.012. 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 (G>C, Δ0.24 donor 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 **0.00161%** (nfe) · FAF95 0.00103% · FAF99 0.000832% · 19/1,177,284 in the highest group · 22/1,609,158 alleles overall — very rare (popmax 0.00161%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00161% | 61,962 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,186 |
| African / African-American | 0.00134% | 74,610 |
| South Asian | 0.0011% | 90,960 |

*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}

**ARMC8** population constraint: LOEUF 0.317, pLI 1, missense-Z 3.0345. *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 **161** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 94.16, 92% of residues very-high.

**1 experimental structure(s)** (PDB): [7NSC](https://www.rcsb.org/structure/7NSC).

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

*Describes the biological roles of ARMC8 (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}

ARMC8 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | other |
| [Regulation of pyruvate metabolism](https://reactome.org/content/detail/R-HSA-9861718) | other |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-21.

**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 | 2023-06-21 |

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

## Similar variants {#similar}

Related ARMC8 variant pages (same residue, condition, or type): [ARMC8 p.Ala403Thr](/variant/armc8-p-ala403thr), [ARMC8 p.Ala469Thr](/variant/armc8-p-ala469thr), [ARMC8 p.Arg159Lys](/variant/armc8-p-arg159lys), [ARMC8 p.Arg270Gln](/variant/armc8-p-arg270gln), [ARMC8 p.Arg270Trp](/variant/armc8-p-arg270trp), [ARMC8 p.Arg376Trp](/variant/armc8-p-arg376trp), [ARMC8 p.Arg542Cys](/variant/armc8-p-arg542cys), [ARMC8 p.Asp591His](/variant/armc8-p-asp591his).

### 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 2604768). 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.*