# NM_144670.6(A2ML1):c.1444_1445del (p.Ser482fs)

https://sugi.bio/variant/a2ml1-p-ser482fs

## Summary

**A2ML1 p.Ser482fs (c.1444_1445del)** is classified **Benign** in A2ML1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). Common (popmax 5.75%, afr) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs143864957 · 4 submitters · common (popmax 5.75%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the A2ML1 gene that is classified as benign — not considered disease-causing, submitted by 4 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 | [A2ML1](https://sugi.bio/atlas/gene/A2ML1/) |
| Protein change (HGVS p.) | p.Ser482fs |
| Coding change (HGVS c.) | c.1444_1445del |
| MANE Select transcript | [NM_144670](https://www.ncbi.nlm.nih.gov/nuccore/NM_144670) |
| dbSNP | [rs143864957](https://www.ncbi.nlm.nih.gov/snp/rs143864957/) |
| Variant type | Deletion |
| Location | chr12:8843329-8843330 (GRCh38) |
| ClinVar | [VCV241884](https://www.ncbi.nlm.nih.gov/clinvar/variation/241884/) |

**All HGVS expressions:** `NC_000012.11:g.8995925_8995926del`, `NC_000012.12:g.8843329_8843330del`, `NG_042857.1:g.25858_25859del`, `NM_144670.4:c.1444_1445del`, `NM_144670.5:c.1444_1445delAG`, `NM_144670.6:c.1444_1445del`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 5.75%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 -3.855, GERP -3.2 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.953, pLI 1.7127e-40. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 12 of 36**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 20.8**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **5.75%** (afr) · FAF95 5.61% · FAF99 5.55% · 4,316/75,006 in the highest group · 4,831/1,614,136 alleles overall — common (popmax 5.75%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 5.75% | 17 |
| Admixed American | 0.345% | 290 |
| Remaining individuals (not grpmax-eligible) | 0.309% | 324 |
| Middle Eastern | 0.182% | 551 |
| European (non-Finnish) | 0.00839% | 11,919 |
| South Asian | 0.00439% | 22,772 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,042 |

*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}

**A2ML1** population constraint: LOEUF 0.953, pLI 1.7127e-40, missense-Z 1.6571. *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):

- **Noonan syndrome** — Disputed (AD)

## Protein context {#protein}

Residue **482** lies in a disulfide bond; a UniProt-annotated variant site (risk factor for otitis media).

AlphaFold model confidence (whole protein): pLDDT 80.61, 27% of residues very-high.

**5 experimental structure(s)** (PDB): [7Q1Y](https://www.rcsb.org/structure/7Q1Y), [7Q5Z](https://www.rcsb.org/structure/7Q5Z), [7Q60](https://www.rcsb.org/structure/7Q60), [7Q61](https://www.rcsb.org/structure/7Q61), [7Q62](https://www.rcsb.org/structure/7Q62).

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

*Describes the biological roles of A2ML1 (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:** A2ML1's established molecular role includes peptidase inhibitor activity.


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

**Molecular function:** peptidase inhibitor activity.

**Biological process:** regulation of endopeptidase activity.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-01.

**Submitter consensus:** unanimous (4/4 Benign).

**Submission history:** 4 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2019-08-19 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-03-27 |
| Dubai Health Genomic Medicine Center, Dubai Health | Benign | criteria provided, single submitter | clinical testing | 2020-01-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |

**Reported phenotype names (ClinVar):** not specified, not provided, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related A2ML1 variant pages (same residue, condition, or type): [A2ML1 p.Ser482Arg](/variant/a2ml1-p-ser482arg), [A2ML1 c.3718-2del](/variant/a2ml1-c-3718-minus-2del), [A2ML1 c.2764+20del](/variant/a2ml1-c-2764-plus-20del), [A2ML1 c.4061+11_4061+12del](/variant/a2ml1-c-4061-plus-11-4061-plus-12del), [A2ML1 p.Ala1226fs](/variant/a2ml1-p-ala1226fs), [A2ML1 c.2234+2del](/variant/a2ml1-c-2234-plus-2del), [A2ML1 c.63-16_63-14del](/variant/a2ml1-c-63-minus-16-63-minus-14del), [A2ML1 p.Ala593fs](/variant/a2ml1-p-ala593fs).

### 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 241884). 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.*