# NM_001385682.1(MAP4):c.6374C>T (p.Pro2125Leu)

https://sugi.bio/variant/map4-p-pro2125leu

## Summary

**MAP4 p.Pro2125Leu (c.6374C>T)** is classified **Uncertain significance** in MAP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-10). AlphaMissense: likely benign (0.1082); Ultra-rare (popmax 0.024%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs373072815 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.024%, afr)

## 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.Pro2125Leu |
| Coding change (HGVS c.) | c.6374C>T |
| MANE Select transcript | [NM_001385682](https://www.ncbi.nlm.nih.gov/nuccore/NM_001385682) |
| dbSNP | [rs373072815](https://www.ncbi.nlm.nih.gov/snp/rs373072815/) |
| Variant type | single nucleotide variant |
| Location | chr3:47869248-47869248 (GRCh38) |
| ClinVar | [VCV2459998](https://www.ncbi.nlm.nih.gov/clinvar/variation/2459998/) |

**All HGVS expressions:** `NC_000003.11:g.47910738G>A`, `NC_000003.12:g.47869248G>A`, `NG_052840.1:g.225032C>T`, `NM_001134364.2:c.2939C>T`, `NM_001384675.1:c.2736+1565C>T`, `NM_001384676.1:c.2894C>T`, `NM_001384677.1:c.2814+1610C>T`, `NM_001384678.1:c.2895+1565C>T`, `NM_001384679.1:c.2945C>T`, `NM_001384680.1:c.2633C>T`, `NM_001384681.1:c.2816C>T`, `NM_001384707.1:c.2741C>T`, `NM_001384729.1:c.2939C>T`, `NM_001384730.1:c.2870C>T`, `NM_001384731.1:c.2945C>T`, `NM_001384733.1:c.2784+1565C>T`, `NM_001384734.1:c.2859+1565C>T`, `NM_001384735.1:c.2859+1565C>T`, `NM_001384736.1:c.2990C>T`, `NM_001384737.1:c.2864C>T`, `NM_001384738.1:c.2975C>T`, `NM_001384744.1:c.2867C>T`, `NM_001384745.1:c.3026C>T`, `NM_001384746.1:c.2702C>T`, `NM_001384748.1:c.2975C>T`, `NM_001384751.1:c.2859+1565C>T`, `NM_001384752.1:c.2643+1565C>T`, `NM_001384753.1:c.2627C>T`, `NM_001384754.1:c.2939C>T`, `NM_001384755.1:c.2736+1565C>T`, `NM_001384756.1:c.2894C>T`, `NM_001384757.1:c.2667+1565C>T`, `NM_001384758.1:c.2700+1610C>T`, `NM_001384759.1:c.2616+1610C>T`, `NM_001384760.1:c.2520+1565C>T`, `NM_001384761.1:c.2784+1565C>T`, `NM_001384762.1:c.1635+1565C>T`, `NM_001384774.1:c.2894C>T`, `NM_001384776.1:c.2768C>T`, `NM_001384777.1:c.2870C>T`, `NM_001384778.1:c.2306C>T`, `NM_001384779.1:c.2723C>T`, `NM_001384780.1:c.2654C>T`, `NM_001384781.1:c.2939C>T`, `NM_001384782.1:c.2825C>T`, `NM_001384783.1:c.2790+1565C>T`, `NM_001384784.1:c.1374+1610C>T`, `NM_001384785.1:c.2598+1610C>T`, `NM_001384786.1:c.2790+1565C>T`, `NM_001384787.1:c.2574+1565C>T`, `NM_001384788.1:c.2990C>T`, `NM_001384789.1:c.2526+1610C>T`, `NM_001384790.1:c.2910+1565C>T`, `NM_001384791.1:c.2867C>T`, `NM_001384792.1:c.2910+1565C>T`, `NM_001384793.1:c.2667+1610C>T`, `NM_001384794.1:c.2694+1565C>T`, `NM_001384795.1:c.3026C>T`, `NM_001384796.1:c.2910+1565C>T`, `NM_001384797.1:c.2822C>T`, `NM_001384798.1:c.2939C>T`, `NM_001384800.1:c.2814+1610C>T`, `NM_001384802.1:c.1469C>T`, `NM_001384803.1:c.2622+1565C>T`, `NM_001384804.1:c.2699C>T`, `NM_001384805.1:c.2520+1565C>T`, `NM_001384806.1:c.2736+1565C>T`, `NM_001384807.1:c.2622+1565C>T`, `NM_001384808.1:c.1469C>T`, `NM_001384809.1:c.2643+1565C>T`, `NM_001384810.1:c.2859+1565C>T`, `NM_001384811.1:c.2574+1565C>T`, `NM_001384812.1:c.1344+1610C>T`, `NM_001384813.1:c.1637C>T`, `NM_001384814.1:c.2859+1565C>T`, `NM_001384815.1:c.1389+1565C>T`, `NM_001384816.1:c.2870C>T`, `NM_001384817.1:c.1355C>T`, `NM_001384819.1:c.2859+1565C>T`, `NM_001384820.1:c.2864C>T`, `NM_001384824.1:c.2784+1565C>T`, `NM_001384825.1:c.2745+1565C>T`, `NM_001384826.1:c.2520+1565C>T`, `NM_001384827.1:c.2787+1565C>T`, `NM_001384828.1:c.2790+1565C>T`, `NM_001384831.1:c.2678C>T`, `NM_001384832.1:c.2825C>T`, `NM_001384834.1:c.2849C>T`, `NM_001384835.1:c.1173+1565C>T`, `NM_001384836.1:c.2816C>T`, `NM_001384837.1:c.2771C>T`, `NM_001384838.1:c.2912C>T`, `NM_001384839.1:c.2618C>T`, `NM_001384840.1:c.2643+1565C>T`, `NM_001384841.1:c.2700+1610C>T`, `NM_001384842.1:c.2486C>T`, `NM_001384843.1:c.2702C>T`, `NM_001384844.1:c.2643+1565C>T`, `NM_001384845.1:c.2573C>T`, `NM_001384846.1:c.2814+1610C>T`, `NM_001384847.1:c.2723C>T`, `NM_001384848.1:c.2859+1565C>T`, `NM_001384849.1:c.2900C>T`, `NM_001384850.1:c.2741C>T`, `NM_001384851.1:c.2609C>T`, `NM_001384853.1:c.2691+1610C>T`, `NM_001384856.1:c.2226+1565C>T`, `NM_001384857.1:c.2745+1610C>T`, `NM_001384859.1:c.2736+1610C>T`, `NM_001384861.1:c.2598+1610C>T`, `NM_001384862.1:c.2340+1565C>T`, `NM_001384863.1:c.2943+1565C>T`, `NM_001384864.1:c.2747C>T`, `NM_001384866.1:c.2600C>T`, `NM_001384867.1:c.2618C>T`, `NM_001384868.1:c.2816C>T`, `NM_001384869.1:c.2790+1565C>T`, `NM_001384870.1:c.2643+1565C>T`, `NM_001384871.1:c.2867C>T`, `NM_001384872.1:c.2850+1610C>T`, `NM_001384873.1:c.2861C>T`, `NM_001384874.1:c.2769+1565C>T`, `NM_001384875.1:c.2930C>T`, `NM_001384876.1:c.2825C>T`, `NM_001384877.1:c.1592C>T`, `NM_001384878.1:c.2736+1565C>T`, `NM_001384879.1:c.2939C>T`, `NM_001384892.1:c.2849C>T`, `NM_001384893.1:c.2691+1610C>T`, `NM_001385664.1:c.6174+1565C>T`, `NM_001385665.1:c.2939C>T`, `NM_001385675.1:c.2895+1565C>T`, `NM_001385676.1:c.2531C>T`, `NM_001385677.1:c.2859+1565C>T`, `NM_001385681.1:c.2910+1565C>T`, `NM_001385682.1:c.6374C>T`, `NM_001385684.1:c.2814+1610C>T`, `NM_001385685.1:c.2723C>T`, `NM_001385686.1:c.2990C>T`, `NM_001385687.1:c.6374C>T`, `NM_001385688.1:c.6177+1610C>T`, `NM_001385689.1:c.6294+1565C>T`, `NM_002375.5:c.2939C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1082)
- REVEL 0.183 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.352 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.604, GERP 2.28, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P980L** vs ClinVar **P2125L**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 22.6**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.22 donor 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 **0.024%** (afr) · FAF95 0.0155% · FAF99 0.0128% · 18/74,900 in the highest group · 19/1,613,930 alleles overall — ultra-rare (popmax 0.024%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.024% | 4,161 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |

*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 **980** lies in the 'disordered' region.

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 2023-02-10.

**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 | 2023-02-10 |

**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 2026-10-14); 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 2459998). 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.*