# NM_032131.6(ARMC2):c.297G>A (p.Pro99=)

https://sugi.bio/variant/armc2-p-pro99

## Summary

**ARMC2 p.Pro99= (c.297G>A)** is classified **Benign** in ARMC2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-05-16). Low-frequency (popmax 1.63%, afr); Associated with ARMC2-related disorder.

**At a glance:** Benign · review: No assertion criteria · rsID rs73524086 · 1 submitter · 1 linked condition · low-frequency (popmax 1.63%, afr)

## For patients & families {#patients}

This is a change in the ARMC2 gene that is classified as benign — not considered disease-causing, submitted by 1 submitter, and is linked to ARMC2-related disorder.

*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 | [ARMC2](https://sugi.bio/atlas/gene/ARMC2/) |
| Protein change (HGVS p.) | p.Pro99= |
| Coding change (HGVS c.) | c.297G>A |
| MANE Select transcript | [NM_032131](https://www.ncbi.nlm.nih.gov/nuccore/NM_032131) |
| dbSNP | [rs73524086](https://www.ncbi.nlm.nih.gov/snp/rs73524086/) |
| Variant type | single nucleotide variant |
| Location | chr6:108868829-108868829 (GRCh38) |
| ClinVar | [VCV3033187](https://www.ncbi.nlm.nih.gov/clinvar/variation/3033187/) |

**All HGVS expressions:** `NC_000006.11:g.109190032G>A`, `NC_000006.12:g.108868829G>A`, `NM_001286609.2:c.-199G>A`, `NM_032131.6:c.297G>A`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -3.954, GERP -5.08 — fast-evolving / accelerated position
- CADD: **PHRED 4.828**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, 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 **1.63%** (afr) · FAF95 1.55% · FAF99 1.52% · 1,212/74,542 in the highest group · 1,358/1,608,220 alleles overall — low-frequency (popmax 1.63%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.63% | 62 |
| Admixed American | 0.124% | 806 |
| Remaining individuals (not grpmax-eligible) | 0.0772% | 1,295 |
| South Asian | 0.00776% | 12,889 |
| European (non-Finnish) | 0.00161% | 62,016 |

*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}

**ARMC2** population constraint: LOEUF 0.936, pLI 1.6643e-15, missense-Z 1.587. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **spermatogenic failure 38** — Definitive (AR)

## Protein context {#protein}

Residue **99** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 75.57, 55% of residues very-high.

## Clinical significance {#significance}

**Benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-05-16.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2024-05-16 |

## Associated conditions {#conditions}

[ARMC2-related disorder](https://sugi.bio/atlas/disease/armc2-related-disorder/).

**Reported phenotype names (ClinVar):** ARMC2-related disorder, ARMC2-related condition.

## Similar variants {#similar}

Related ARMC2 variant pages (same residue, condition, or type): [ARMC2 p.Pro99Leu](/variant/armc2-p-pro99leu), [ARMC2 p.Ile185Val](/variant/armc2-p-ile185val), [ARMC2 c.219-4C>T](/variant/armc2-c-219-minus-4c-t), [ARMC2 p.Ala184Val](/variant/armc2-p-ala184val), [ARMC2 p.Ala593=](/variant/armc2-p-ala593), [ARMC2 p.Gly438=](/variant/armc2-p-gly438), [ARMC2 p.Ile630Val](/variant/armc2-p-ile630val), [ARMC2 p.Met166Thr](/variant/armc2-p-met166thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3033187). 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.*