# NM_001385682.1(MAP4):c.6479A>G (p.Lys2160Arg)

https://sugi.bio/variant/map4-p-lys2160arg

## Summary

**MAP4 p.Lys2160Arg (c.6479A>G)** is classified **Uncertain significance** in MAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.2933); Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the MAP4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [MAP4](https://sugi.bio/atlas/gene/MAP4/) |
| Protein change (HGVS p.) | p.Lys2160Arg |
| Coding change (HGVS c.) | c.6479A>G |
| MANE Select transcript | [NM_001385682](https://www.ncbi.nlm.nih.gov/nuccore/NM_001385682) |
| Variant type | single nucleotide variant |
| Location | chr3:47867268-47867268 (GRCh38) |
| ClinVar | [VCV4051412](https://www.ncbi.nlm.nih.gov/clinvar/variation/4051412/) |

**All HGVS expressions:** `NC_000003.11:g.47908758T>C`, `NC_000003.12:g.47867268T>C`, `NG_052840.1:g.227012A>G`, `NM_001134364.2:c.3044A>G`, `NM_001384675.1:c.2736+3545A>G`, `NM_001384676.1:c.2999A>G`, `NM_001384677.1:c.2814+3590A>G`, `NM_001384678.1:c.2895+3545A>G`, `NM_001384679.1:c.3050A>G`, `NM_001384680.1:c.2738A>G`, `NM_001384681.1:c.2921A>G`, `NM_001384707.1:c.2846A>G`, `NM_001384729.1:c.3044A>G`, `NM_001384730.1:c.2975A>G`, `NM_001384731.1:c.3050A>G`, `NM_001384733.1:c.2784+3545A>G`, `NM_001384734.1:c.2930A>G`, `NM_001384735.1:c.2859+3545A>G`, `NM_001384736.1:c.3095A>G`, `NM_001384737.1:c.2969A>G`, `NM_001384738.1:c.3080A>G`, `NM_001384744.1:c.2972A>G`, `NM_001384745.1:c.3131A>G`, `NM_001384746.1:c.2807A>G`, `NM_001384748.1:c.3080A>G`, `NM_001384751.1:c.2859+3545A>G`, `NM_001384752.1:c.2643+3545A>G`, `NM_001384753.1:c.2732A>G`, `NM_001384754.1:c.2973+1946A>G`, `NM_001384755.1:c.2736+3545A>G`, `NM_001384756.1:c.2999A>G`, `NM_001384757.1:c.2667+3545A>G`, `NM_001384758.1:c.2700+3590A>G`, `NM_001384759.1:c.2616+3590A>G`, `NM_001384760.1:c.2520+3545A>G`, `NM_001384761.1:c.2784+3545A>G`, `NM_001384762.1:c.1635+3545A>G`, `NM_001384774.1:c.2999A>G`, `NM_001384776.1:c.2873A>G`, `NM_001384777.1:c.2904+1946A>G`, `NM_001384778.1:c.2411A>G`, `NM_001384779.1:c.2828A>G`, `NM_001384780.1:c.2759A>G`, `NM_001384781.1:c.2973+1946A>G`, `NM_001384782.1:c.2930A>G`, `NM_001384783.1:c.2790+3545A>G`, `NM_001384784.1:c.1374+3590A>G`, `NM_001384785.1:c.2598+3590A>G`, `NM_001384786.1:c.2861A>G`, `NM_001384787.1:c.2574+3545A>G`, `NM_001384788.1:c.3095A>G`, `NM_001384789.1:c.2526+3590A>G`, `NM_001384790.1:c.2910+3545A>G`, `NM_001384791.1:c.2972A>G`, `NM_001384792.1:c.2910+3545A>G`, `NM_001384793.1:c.2667+3590A>G`, `NM_001384794.1:c.2765A>G`, `NM_001384795.1:c.3131A>G`, `NM_001384796.1:c.2981A>G`, `NM_001384797.1:c.2927A>G`, `NM_001384798.1:c.3044A>G`, `NM_001384800.1:c.2814+3590A>G`, `NM_001384802.1:c.1574A>G`, `NM_001384803.1:c.2622+3545A>G`, `NM_001384804.1:c.2804A>G`, `NM_001384805.1:c.2520+3545A>G`, `NM_001384806.1:c.2807A>G`, `NM_001384807.1:c.2622+3545A>G`, `NM_001384808.1:c.1574A>G`, `NM_001384809.1:c.2643+3545A>G`, `NM_001384810.1:c.2859+3545A>G`, `NM_001384811.1:c.2574+3545A>G`, `NM_001384812.1:c.1344+3590A>G`, `NM_001384813.1:c.1742A>G`, `NM_001384814.1:c.2930A>G`, `NM_001384815.1:c.1389+3545A>G`, `NM_001384816.1:c.2975A>G`, `NM_001384817.1:c.1460A>G`, `NM_001384819.1:c.2859+3545A>G`, `NM_001384820.1:c.2969A>G`, `NM_001384824.1:c.2855A>G`, `NM_001384825.1:c.2745+3545A>G`, `NM_001384826.1:c.2591A>G`, `NM_001384827.1:c.2787+3545A>G`, `NM_001384828.1:c.2861A>G`, `NM_001384831.1:c.2783A>G`, `NM_001384832.1:c.2930A>G`, `NM_001384834.1:c.2954A>G`, `NM_001384835.1:c.1173+3545A>G`, `NM_001384836.1:c.2921A>G`, `NM_001384837.1:c.2876A>G`, `NM_001384838.1:c.3017A>G`, `NM_001384839.1:c.2723A>G`, `NM_001384840.1:c.2714A>G`, `NM_001384841.1:c.2700+3590A>G`, `NM_001384842.1:c.2591A>G`, `NM_001384843.1:c.2807A>G`, `NM_001384844.1:c.2643+3545A>G`, `NM_001384845.1:c.2678A>G`, `NM_001384846.1:c.2885A>G`, `NM_001384847.1:c.2828A>G`, `NM_001384848.1:c.2859+3545A>G`, `NM_001384849.1:c.3005A>G`, `NM_001384850.1:c.2846A>G`, `NM_001384851.1:c.2714A>G`, `NM_001384853.1:c.2762A>G`, `NM_001384856.1:c.2226+3545A>G`, `NM_001384857.1:c.2745+3590A>G`, `NM_001384859.1:c.2736+3590A>G`, `NM_001384861.1:c.2598+3590A>G`, `NM_001384862.1:c.2340+3545A>G`, `NM_001384863.1:c.2943+3545A>G`, `NM_001384864.1:c.2852A>G`, `NM_001384866.1:c.2705A>G`, `NM_001384867.1:c.2723A>G`, `NM_001384868.1:c.2921A>G`, `NM_001384869.1:c.2790+3545A>G`, `NM_001384870.1:c.2714A>G`, `NM_001384871.1:c.2972A>G`, `NM_001384872.1:c.2850+3590A>G`, `NM_001384873.1:c.2966A>G`, `NM_001384874.1:c.2840A>G`, `NM_001384875.1:c.3035A>G`, `NM_001384876.1:c.2930A>G`, `NM_001384877.1:c.1697A>G`, `NM_001384878.1:c.2736+3545A>G`, `NM_001384879.1:c.3044A>G`, `NM_001384892.1:c.2954A>G`, `NM_001384893.1:c.2691+3590A>G`, `NM_001385664.1:c.6245A>G`, `NM_001385665.1:c.3044A>G`, `NM_001385675.1:c.2966A>G`, `NM_001385676.1:c.2636A>G`, `NM_001385677.1:c.2930A>G`, `NM_001385681.1:c.2981A>G`, `NM_001385682.1:c.6479A>G`, `NM_001385684.1:c.2885A>G`, `NM_001385685.1:c.2828A>G`, `NM_001385686.1:c.3095A>G`, `NM_001385687.1:c.6479A>G`, `NM_001385688.1:c.6248A>G`, `NM_001385689.1:c.6365A>G`, `NM_002375.5:c.3044A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2933)
- REVEL 0.817 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -7.327 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- SpliceAI predicts **donor loss** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.87, GERP 2.28, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **K1015R** vs ClinVar **K2160R**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 27.2**. 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.*
- Regional missense constraint: **o/e 0.95** across the covering region of the MANE Select transcript (47,852,937–47,875,761), spanning 22,824 bp. Chi-square p 0.28. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.24**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 22 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, 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.*
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.000124% · FAF99 9e-05% · 1/6,052 in the highest group · 7/1,613,092 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,052 |
| South Asian | 0.0011% | 90,994 |
| European (non-Finnish) | 0.000424% | 235,822 |

*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}

**MAP4** population constraint: LOEUF 0.512, pLI 0.13681, missense-Z 2.4555. *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 43.03, 0% of residues very-high.

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

*Describes the biological roles of MAP4 (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:** MAP4's established molecular role includes RNA binding.


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

**Molecular function:** RNA binding, microtubule stabilizing activity.

**Biological process:** microtubule cytoskeleton organization, mitotic spindle organization, microtubule polymerization, microtubule sliding, establishment of spindle orientation, cell division.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-05.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-05 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related MAP4 variant pages (same residue, condition, or type): [MAP4 c.292+9T>G](/variant/map4-c-292-plus-9t-g), [MAP4 p.Gln1950=](/variant/map4-p-gln1950), [MAP4 p.Leu516=](/variant/map4-p-leu516), [MAP4 p.Val37=](/variant/map4-p-val37), [MAP4 p.Ala150Ser](/variant/map4-p-ala150ser), [MAP4 p.Ala1922Val](/variant/map4-p-ala1922val), [MAP4 p.Ala1926Pro](/variant/map4-p-ala1926pro), [MAP4 p.Ala1941Thr](/variant/map4-p-ala1941thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4051412). 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.*