# NM_144670.6(A2ML1):c.633G>A (p.Val211=)

https://sugi.bio/variant/a2ml1-p-val211

## Summary

**A2ML1 p.Val211= (c.633G>A)** is classified **Benign** in A2ML1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Low-frequency (popmax 1.69%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs79151946 · 5 submitters · low-frequency (popmax 1.69%, afr)

## For patients & families {#patients}

This is a change in the A2ML1 gene that is classified as benign — not considered disease-causing, submitted by 5 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.Val211= |
| Coding change (HGVS c.) | c.633G>A |
| MANE Select transcript | [NM_144670](https://www.ncbi.nlm.nih.gov/nuccore/NM_144670) |
| dbSNP | [rs79151946](https://www.ncbi.nlm.nih.gov/snp/rs79151946/) |
| Variant type | single nucleotide variant |
| Location | chr12:8835656-8835656 (GRCh38) |
| ClinVar | [VCV413813](https://www.ncbi.nlm.nih.gov/clinvar/variation/413813/) |

**All HGVS expressions:** `NC_000012.11:g.8988252G>A`, `NC_000012.12:g.8835656G>A`, `NG_042857.1:g.18185G>A`, `NM_144670.6:c.633G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 3, GERP 0.457, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 4.794**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 10 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.19**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.24** (loss), gain 0.00 / loss 0.24. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **1.69%** (afr) · FAF95 1.61% · FAF99 1.58% · 1,266/75,024 in the highest group · 1,470/1,614,106 alleles overall — low-frequency (popmax 1.69%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.69% | 59 |
| Admixed American | 0.183% | 546 |
| Remaining individuals (not grpmax-eligible) | 0.118% | 845 |
| Middle Eastern | 0.0826% | 1,211 |
| South Asian | 0.00329% | 30,359 |
| European (non-Finnish) | 0.00102% | 98,333 |

*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 **211** lies in a β-strand.

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 2026-02-02.

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

**Submission history:** 5 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2017-04-10 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2020-07-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-08-07 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

**Reported phenotype names (ClinVar):** not specified, not provided, A2ML1-related disorder, Melanoma, A2ML1-related condition, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related A2ML1 variant pages (same residue, condition, or type): [A2ML1 p.Val211Met](/variant/a2ml1-p-val211met), [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 413813). 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.*