# NM_005360.5(MAF):c.188C>G (p.Pro63Arg)

https://sugi.bio/variant/maf-p-pro63arg

## Summary

**MAF p.Pro63Arg (c.188C>G)** is classified **Likely pathogenic** in MAF (ClinVar, Single submitter, 1 submitter; last evaluated 2015-07-22). AlphaMissense: likely pathogenic (0.9989); Absent from gnomAD v4.1; Associated with Developmental cataract.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1057518878 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MAF gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Developmental cataract.

*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 | [MAF](https://sugi.bio/atlas/gene/MAF/) |
| Protein change (HGVS p.) | p.Pro63Arg |
| Coding change (HGVS c.) | c.188C>G |
| MANE Select transcript | [NM_005360](https://www.ncbi.nlm.nih.gov/nuccore/NM_005360) |
| dbSNP | [rs1057518878](https://www.ncbi.nlm.nih.gov/snp/rs1057518878/) |
| Variant type | single nucleotide variant |
| Location | chr16:79599715-79599715 (GRCh38) |
| ClinVar | [VCV374075](https://www.ncbi.nlm.nih.gov/clinvar/variation/374075/) |

**All HGVS expressions:** `NC_000016.10:g.79599715G>C`, `NC_000016.9:g.79633612G>C`, `NG_016440.1:g.6011C>G`, `NM_001031804.3:c.188C>G`, `NM_005360.5:c.188C>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9989) — concordant with the pathogenic call
- REVEL 0.903 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.14 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 10.94, GERP 2.24, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in MAF (of 2,213 modeled).
- CADD: **PHRED 32.0**. 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 0.25** across the covering region of the MANE Select transcript (79,599,706–79,599,739), spanning 33 bp — the region is depleted of missense variation. Chi-square p 0.0024. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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}

**MAF** population constraint: LOEUF 0.852, pLI 0.028112, missense-Z -0.25296. *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 **63** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 62.21, 29% of residues very-high.

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

*Describes the biological roles of MAF (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:** MAF's established molecular role includes identical protein binding. p.Pro63Arg falls in the disordered region.


### Pathways affected {#pathways}

MAF participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Affinity selection of immunoglobulins](https://reactome.org/content/detail/R-HSA-9938027) | electronic |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [RUNX2 regulates osteoblast differentiation](https://reactome.org/content/detail/R-HSA-8940973) | electronic |

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

**Molecular function:** identical protein binding, sequence-specific double-stranded DNA binding.

**Biological process:** megakaryocyte differentiation.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2015-07-22.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Likely pathogenic | criteria provided, single submitter | clinical testing | 2015-07-22 |

## Associated conditions {#conditions}

[Developmental cataract](https://sugi.bio/atlas/disease/developmental-cataract/).

**Reported phenotype names (ClinVar):** Developmental cataract, Congenital cataracts, Bilateral cataracts, Congenital cataract.

## Similar variants {#similar}

Related MAF variant pages (same residue, condition, or type): [MAF p.Arg294Trp](/variant/maf-p-arg294trp), [MAF p.Cys305=](/variant/maf-p-cys305), [MAF p.Glu273Asp](/variant/maf-p-glu273asp), [MAF p.Ala302Val](/variant/maf-p-ala302val), [MAF p.Arg299Cys](/variant/maf-p-arg299cys), [MAF p.Arg306Gly](/variant/maf-p-arg306gly), [MAF p.Cys305Phe](/variant/maf-p-cys305phe), [MAF p.Pro59His](/variant/maf-p-pro59his).

### 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 374075). 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.*