# NM_201589.4(MAFA):c.191C>T (p.Ser64Phe)

https://sugi.bio/variant/mafa-p-ser64phe

## Summary

**MAFA p.Ser64Phe (c.191C>T)** is classified **Likely pathogenic** in MAFA (ClinVar, Single submitter, 2 submitters; last evaluated 2018-10-15). AlphaMissense: likely pathogenic (0.995); No allele count reported in gnomAD v4.1 (AN 1,315,704); Associated with islet cell adenomatosis.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1554635488 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,315,704)

## For patients & families {#patients}

This is a change in the MAFA gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to islet cell adenomatosis.

*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 | [MAFA](https://sugi.bio/atlas/gene/MAFA/) |
| Protein change (HGVS p.) | p.Ser64Phe |
| Coding change (HGVS c.) | c.191C>T |
| MANE Select transcript | [NM_201589](https://www.ncbi.nlm.nih.gov/nuccore/NM_201589) |
| dbSNP | [rs1554635488](https://www.ncbi.nlm.nih.gov/snp/rs1554635488/) |
| Variant type | single nucleotide variant |
| Location | chr8:143430216-143430216 (GRCh38) |
| ClinVar | [VCV496645](https://www.ncbi.nlm.nih.gov/clinvar/variation/496645/) |

**All HGVS expressions:** `NC_000008.10:g.144512386G>A`, `NC_000008.11:g.143430216G>A`, `NM_201589.4:c.191C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.995) — concordant with the pathogenic call
- REVEL 0.589 (indeterminate)
- SaProt LLR -13.745 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 8.926, GERP 0.666, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.6**. 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 0.42** across the covering region of the MANE Select transcript (143,430,166–143,430,261), spanning 95 bp. Chi-square p 6.1e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,315,704)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}


## Protein context {#protein}

Residue **64** lies in a UniProt-annotated variant site (in insdm; may prevent phosphorylation at s-65; may enhance protein stability); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 64.06, 30% of residues very-high.

**1 experimental structure(s)** (PDB): [4EOT](https://www.rcsb.org/structure/4EOT).

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

*Describes the biological roles of MAFA (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:** MAFA's established molecular role includes DNA binding. p.Ser64Phe falls in the disordered region.


### Pathways affected {#pathways}

MAFA participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of gene expression in beta cells](https://reactome.org/content/detail/R-HSA-210745) | electronic |

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

**Molecular function:** DNA binding, DNA-binding transcription factor activity, sequence-specific double-stranded DNA binding.

**Biological process:** response to glucose, insulin secretion, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-10-15.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2018); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2018-03-19 |
| SIB Swiss Institute of Bioinformatics | Likely pathogenic | criteria provided, single submitter | curation | 2018-10-15 |

## Associated conditions {#conditions}

[islet cell adenomatosis](https://sugi.bio/atlas/disease/islet-cell-adenomatosis/).

**Reported phenotype names (ClinVar):** Islet cell adenomatosis.

## Similar variants {#similar}

Related MAFA variant pages (same residue, condition, or type): [MAFA p.Ala211Thr](/variant/mafa-p-ala211thr), [MAFA p.Thr57Arg](/variant/mafa-p-thr57arg), [MAFA p.Ala138Glu](/variant/mafa-p-ala138glu), [MAFA p.Phe41Val](/variant/mafa-p-phe41val), [MAFA p.Ser61Phe](/variant/mafa-p-ser61phe), [MAFA p.Gly266Cys](/variant/mafa-p-gly266cys), [MAFA p.His206_His208del](/variant/mafa-p-his206-his208del), [MAFA p.Arg333Trp](/variant/mafa-p-arg333trp).

### 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 496645). 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.*