# NM_144670.6(A2ML1):c.4023G>A (p.Pro1341=)

https://sugi.bio/variant/a2ml1-p-pro1341

## Summary

**A2ML1 p.Pro1341= (c.4023G>A)** is classified **Likely benign** in A2ML1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-13). Very rare (popmax 0.00668%, eas).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs751414888 · 2 submitters · very rare (popmax 0.00668%, eas)

## For patients & families {#patients}

This is a change in the A2ML1 gene that is classified as likely benign — not considered disease-causing, submitted by 2 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.Pro1341= |
| Coding change (HGVS c.) | c.4023G>A |
| MANE Select transcript | [NM_144670](https://www.ncbi.nlm.nih.gov/nuccore/NM_144670) |
| dbSNP | [rs751414888](https://www.ncbi.nlm.nih.gov/snp/rs751414888/) |
| Variant type | single nucleotide variant |
| Location | chr12:8868319-8868319 (GRCh38) |
| ClinVar | [VCV1564495](https://www.ncbi.nlm.nih.gov/clinvar/variation/1564495/) |

**All HGVS expressions:** `NC_000012.11:g.9020915G>A`, `NC_000012.12:g.8868319G>A`, `NG_042857.1:g.50848G>A`, `NM_001282424.3:c.2550G>A`, `NM_144670.6:c.4023G>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 -4.821, GERP -2.41 — fast-evolving / accelerated position
- CADD: **PHRED 0.488**. 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>C, Δ0.27 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 **0.00668%** (eas) · FAF95 0.00177% · FAF99 0.000891% · 3/44,878 in the highest group · 16/1,461,192 alleles overall — very rare (popmax 0.00668%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00668% | 14,959 |
| South Asian | 0.0033% | 30,267 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,482 |
| European (non-Finnish) | 0.000763% | 131,099 |

*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 **1341** 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-10-13.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2019–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-10-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-13 |

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

## Similar variants {#similar}

Related A2ML1 variant pages (same residue, condition, or type): [A2ML1 p.Pro1341Leu](/variant/a2ml1-p-pro1341leu), [A2ML1 c.1834-1G>T](/variant/a2ml1-c-1834-minus-1g-t), [A2ML1 c.3264+4C>T](/variant/a2ml1-c-3264-plus-4c-t), [A2ML1 c.3933+4A>G](/variant/a2ml1-c-3933-plus-4a-g), [A2ML1 c.409+1G>A](/variant/a2ml1-c-409-plus-1g-a), [A2ML1 c.4221+2T>C](/variant/a2ml1-c-4221-plus-2t-c), [A2ML1 c.*1+1G>A](/variant/a2ml1-c-star-1-plus-1g-a), [A2ML1 p.Ala1002Val](/variant/a2ml1-p-ala1002val).

### 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 1564495). 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.*