# NM_001385682.1(MAP4):c.6435C>G (p.Ser2145Arg)

https://sugi.bio/variant/map4-p-ser2145arg

## Summary

**MAP4 p.Ser2145Arg (c.6435C>G)** is classified **Uncertain significance** in MAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely pathogenic (0.9527); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## 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.Ser2145Arg |
| Coding change (HGVS c.) | c.6435C>G |
| MANE Select transcript | [NM_001385682](https://www.ncbi.nlm.nih.gov/nuccore/NM_001385682) |
| Variant type | single nucleotide variant |
| Location | chr3:47867312-47867312 (GRCh38) |
| ClinVar | [VCV4103497](https://www.ncbi.nlm.nih.gov/clinvar/variation/4103497/) |

**All HGVS expressions:** `NC_000003.11:g.47908802G>C`, `NC_000003.12:g.47867312G>C`, `NG_052840.1:g.226968C>G`, `NM_001134364.2:c.3000C>G`, `NM_001384675.1:c.2736+3501C>G`, `NM_001384676.1:c.2955C>G`, `NM_001384677.1:c.2814+3546C>G`, `NM_001384678.1:c.2895+3501C>G`, `NM_001384679.1:c.3006C>G`, `NM_001384680.1:c.2694C>G`, `NM_001384681.1:c.2877C>G`, `NM_001384707.1:c.2802C>G`, `NM_001384729.1:c.3000C>G`, `NM_001384730.1:c.2931C>G`, `NM_001384731.1:c.3006C>G`, `NM_001384733.1:c.2784+3501C>G`, `NM_001384734.1:c.2886C>G`, `NM_001384735.1:c.2859+3501C>G`, `NM_001384736.1:c.3051C>G`, `NM_001384737.1:c.2925C>G`, `NM_001384738.1:c.3036C>G`, `NM_001384744.1:c.2928C>G`, `NM_001384745.1:c.3087C>G`, `NM_001384746.1:c.2763C>G`, `NM_001384748.1:c.3036C>G`, `NM_001384751.1:c.2859+3501C>G`, `NM_001384752.1:c.2643+3501C>G`, `NM_001384753.1:c.2688C>G`, `NM_001384754.1:c.2973+1902C>G`, `NM_001384755.1:c.2736+3501C>G`, `NM_001384756.1:c.2955C>G`, `NM_001384757.1:c.2667+3501C>G`, `NM_001384758.1:c.2700+3546C>G`, `NM_001384759.1:c.2616+3546C>G`, `NM_001384760.1:c.2520+3501C>G`, `NM_001384761.1:c.2784+3501C>G`, `NM_001384762.1:c.1635+3501C>G`, `NM_001384774.1:c.2955C>G`, `NM_001384776.1:c.2829C>G`, `NM_001384777.1:c.2904+1902C>G`, `NM_001384778.1:c.2367C>G`, `NM_001384779.1:c.2784C>G`, `NM_001384780.1:c.2715C>G`, `NM_001384781.1:c.2973+1902C>G`, `NM_001384782.1:c.2886C>G`, `NM_001384783.1:c.2790+3501C>G`, `NM_001384784.1:c.1374+3546C>G`, `NM_001384785.1:c.2598+3546C>G`, `NM_001384786.1:c.2817C>G`, `NM_001384787.1:c.2574+3501C>G`, `NM_001384788.1:c.3051C>G`, `NM_001384789.1:c.2526+3546C>G`, `NM_001384790.1:c.2910+3501C>G`, `NM_001384791.1:c.2928C>G`, `NM_001384792.1:c.2910+3501C>G`, `NM_001384793.1:c.2667+3546C>G`, `NM_001384794.1:c.2721C>G`, `NM_001384795.1:c.3087C>G`, `NM_001384796.1:c.2937C>G`, `NM_001384797.1:c.2883C>G`, `NM_001384798.1:c.3000C>G`, `NM_001384800.1:c.2814+3546C>G`, `NM_001384802.1:c.1530C>G`, `NM_001384803.1:c.2622+3501C>G`, `NM_001384804.1:c.2760C>G`, `NM_001384805.1:c.2520+3501C>G`, `NM_001384806.1:c.2763C>G`, `NM_001384807.1:c.2622+3501C>G`, `NM_001384808.1:c.1530C>G`, `NM_001384809.1:c.2643+3501C>G`, `NM_001384810.1:c.2859+3501C>G`, `NM_001384811.1:c.2574+3501C>G`, `NM_001384812.1:c.1344+3546C>G`, `NM_001384813.1:c.1698C>G`, `NM_001384814.1:c.2886C>G`, `NM_001384815.1:c.1389+3501C>G`, `NM_001384816.1:c.2931C>G`, `NM_001384817.1:c.1416C>G`, `NM_001384819.1:c.2859+3501C>G`, `NM_001384820.1:c.2925C>G`, `NM_001384824.1:c.2811C>G`, `NM_001384825.1:c.2745+3501C>G`, `NM_001384826.1:c.2547C>G`, `NM_001384827.1:c.2787+3501C>G`, `NM_001384828.1:c.2817C>G`, `NM_001384831.1:c.2739C>G`, `NM_001384832.1:c.2886C>G`, `NM_001384834.1:c.2910C>G`, `NM_001384835.1:c.1173+3501C>G`, `NM_001384836.1:c.2877C>G`, `NM_001384837.1:c.2832C>G`, `NM_001384838.1:c.2973C>G`, `NM_001384839.1:c.2679C>G`, `NM_001384840.1:c.2670C>G`, `NM_001384841.1:c.2700+3546C>G`, `NM_001384842.1:c.2547C>G`, `NM_001384843.1:c.2763C>G`, `NM_001384844.1:c.2643+3501C>G`, `NM_001384845.1:c.2634C>G`, `NM_001384846.1:c.2841C>G`, `NM_001384847.1:c.2784C>G`, `NM_001384848.1:c.2859+3501C>G`, `NM_001384849.1:c.2961C>G`, `NM_001384850.1:c.2802C>G`, `NM_001384851.1:c.2670C>G`, `NM_001384853.1:c.2718C>G`, `NM_001384856.1:c.2226+3501C>G`, `NM_001384857.1:c.2745+3546C>G`, `NM_001384859.1:c.2736+3546C>G`, `NM_001384861.1:c.2598+3546C>G`, `NM_001384862.1:c.2340+3501C>G`, `NM_001384863.1:c.2943+3501C>G`, `NM_001384864.1:c.2808C>G`, `NM_001384866.1:c.2661C>G`, `NM_001384867.1:c.2679C>G`, `NM_001384868.1:c.2877C>G`, `NM_001384869.1:c.2790+3501C>G`, `NM_001384870.1:c.2670C>G`, `NM_001384871.1:c.2928C>G`, `NM_001384872.1:c.2850+3546C>G`, `NM_001384873.1:c.2922C>G`, `NM_001384874.1:c.2796C>G`, `NM_001384875.1:c.2991C>G`, `NM_001384876.1:c.2886C>G`, `NM_001384877.1:c.1653C>G`, `NM_001384878.1:c.2736+3501C>G`, `NM_001384879.1:c.3000C>G`, `NM_001384892.1:c.2910C>G`, `NM_001384893.1:c.2691+3546C>G`, `NM_001385664.1:c.6201C>G`, `NM_001385665.1:c.3000C>G`, `NM_001385675.1:c.2922C>G`, `NM_001385676.1:c.2592C>G`, `NM_001385677.1:c.2886C>G`, `NM_001385681.1:c.2937C>G`, `NM_001385682.1:c.6435C>G`, `NM_001385684.1:c.2841C>G`, `NM_001385685.1:c.2784C>G`, `NM_001385686.1:c.3051C>G`, `NM_001385687.1:c.6435C>G`, `NM_001385688.1:c.6204C>G`, `NM_001385689.1:c.6321C>G`, `NM_002375.5:c.3000C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9527)
- REVEL 0.721 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -6.251 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- SpliceAI predicts **acceptor loss** (Δ 0.31) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.8, GERP 1.32, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **S1000R** vs ClinVar **S2145R**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in MAP4 (of 6,746 modeled).
- CADD: **PHRED 25.4**. 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 **0.31**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.31**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

Residue **1000** lies in a modified residue (phosphoserine).

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 2025-08-07.

**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 | 2025-08-07 |

**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 4103497). 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.*