Is MAFB p.Ser175Arg (c.525C>G) pathogenic?

MAFB p.Ser175Arg (c.525C>G) is classified Uncertain significance in MAFB (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: ambiguous (0.4862); Very rare (popmax 0.00105%, nfe); Associated with multicentric carpo-tarsal osteolysis with or without nephropathy.

What condition is associated with MAFB p.Ser175Arg (c.525C>G)?

MAFB p.Ser175Arg (c.525C>G) is associated with multicentric carpo-tarsal osteolysis with or without nephropathy (ClinVar).

How common is MAFB p.Ser175Arg (c.525C>G) in the general population?

MAFB p.Ser175Arg (c.525C>G) is very rare (popmax 0.00105%, nfe) (gnomAD).

What do computational predictors say about MAFB p.Ser175Arg (c.525C>G)?

AlphaMissense predicts ambiguous (score 0.4862) — an in-silico prediction, not a clinical call.

MAFB p.Ser175Arg

c.525C>G · rs886056674 · VCV338409

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4862 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00105%, nfe)

Conditions

multicentric carpo-tarsal osteolysis with or without nephropathy

Computational evidence

Protein change
AlphaMissense	0.4862	ambiguous
REVEL	0.317	indeterminate
SaProt	LLR -8.35	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 0.16, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 710 bp · p 0.00051 · regional, not allelic
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00105% European (non-Finnish) · 12/1,142,580 alleles

Filtering AF 0.00056% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000442%

Overall 0.000882% 12/1,360,324 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MAFB
Protein: p.Ser175Arg
Coding: c.525C>G
MANE Select: NM_005461
dbSNP: rs886056674
Type: single nucleotide variant
Location: chr20:40688326 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 63.87
Residue 175: the 'disordered' region

Full MAFB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

multicentric carpo-tarsal osteolysis with or without nephropathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAFB p.Pro59Leu Pathogenic/Likely pathogenic ★★ same condition
MAFB p.Ser54Leu Pathogenic ★★ ⚠ same condition
MAFB p.Ser70Leu Pathogenic/Likely pathogenic ★★ same condition
MAFB p.Thr62Ala Pathogenic ★★ same condition
MAFB c.-77C>G Uncertain significance ★★ same condition
MAFB p.Ala110Glu Uncertain significance ★★ ⚠ same condition
MAFB p.Ala176Thr Uncertain significance ★★ ⚠ same condition
MAFB p.Ala288Val Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mafb-p-ser175arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown