# NM_004672.5(MAP3K6):c.1215C>T (p.Ala405=)

https://sugi.bio/variant/map3k6-p-ala405

## Summary

**MAP3K6 p.Ala405= (c.1215C>T)** is classified **Benign/Likely benign** in MAP3K6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-25). Low-frequency (popmax 1.54%, afr).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs55972073 · 4 submitters · low-frequency (popmax 1.54%, afr)

## For patients & families {#patients}

This is a change in the MAP3K6 gene that is classified as benign/likely 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 | [MAP3K6](https://sugi.bio/atlas/gene/MAP3K6/) |
| Protein change (HGVS p.) | p.Ala405= |
| Coding change (HGVS c.) | c.1215C>T |
| MANE Select transcript | [NM_004672](https://www.ncbi.nlm.nih.gov/nuccore/NM_004672) |
| dbSNP | [rs55972073](https://www.ncbi.nlm.nih.gov/snp/rs55972073/) |
| Variant type | single nucleotide variant |
| Location | chr1:27362681-27362681 (GRCh38) |
| ClinVar | [VCV718726](https://www.ncbi.nlm.nih.gov/clinvar/variation/718726/) |

**All HGVS expressions:** `LRG_1086:g.10357C>T`, `LRG_1086t1:c.1215C>T`, `NC_000001.10:g.27689172G>A`, `NC_000001.11:g.27362681G>A`, `NG_051309.1:g.10357C>T`, `NM_001297609.2:c.1191C>T`, `NM_004672.5:c.1215C>T`

## 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 -12.767, GERP -2.97 — fast-evolving / accelerated position
- CADD: **PHRED 0.175**. 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, Δ0.54 acceptor gain), 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 **1.54%** (afr) · FAF95 1.47% · FAF99 1.44% · 1,158/74,952 in the highest group · 1,530/1,606,214 alleles overall — low-frequency (popmax 1.54%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.54% | 65 |
| Admixed American | 0.115% | 868 |
| Remaining individuals (not grpmax-eligible) | 0.0884% | 1,131 |
| Middle Eastern | 0.0828% | 1,208 |
| European (non-Finnish) | 0.0202% | 4,940 |
| South Asian | 0.00334% | 29,951 |
| Finnish (not grpmax-eligible) | 0.00315% | 31,716 |
| East Asian | 0.00224% | 44,668 |

*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}

**MAP3K6** population constraint: LOEUF 0.855, pLI 6.3314e-26, missense-Z 1.039. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 75.36, 28% of residues very-high.

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

*Describes the biological roles of MAP3K6 (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:** MAP3K6's established molecular role includes magnesium ion binding.


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

**Molecular function:** magnesium ion binding, MAP kinase kinase kinase activity, ATP binding.

**Biological process:** protein phosphorylation.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-11-25.

**Submitter consensus:** conflicting (3 Benign, 1 Likely benign).

**Submission history:** 4 submissions (2018–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-11-06 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-11-06 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-25 |

**Reported phenotype names (ClinVar):** not provided, MAP3K6-related disorder, not specified, AllHighlyPenetrant, none provided, MAP3K6-related condition.

## Similar variants {#similar}

Related MAP3K6 variant pages (same residue, condition, or type): [MAP3K6 c.1256-2A>G](/variant/map3k6-c-1256-minus-2a-g), [MAP3K6 c.2915+9A>T](/variant/map3k6-c-2915-plus-9a-t), [MAP3K6 p.Arg499Cys](/variant/map3k6-p-arg499cys), [MAP3K6 p.Asn622Lys](/variant/map3k6-p-asn622lys), [MAP3K6 p.Gln1142Arg](/variant/map3k6-p-gln1142arg), [MAP3K6 p.Glu248=](/variant/map3k6-p-glu248), [MAP3K6 p.Leu1249=](/variant/map3k6-p-leu1249), [MAP3K6 p.Pro946Leu](/variant/map3k6-p-pro946leu).

### 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 718726). 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.*