Is MAFA p.His194= (c.582T>C) pathogenic?

MAFA p.His194= (c.582T>C) is classified Benign in MAFA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-21). Common (popmax 99.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with MAFA-related disorder.

What condition is associated with MAFA p.His194= (c.582T>C)?

MAFA p.His194= (c.582T>C) is associated with MAFA-related disorder (ClinVar).

MAFA p.His194=

Q: How common is MAFA p.His194= (c.582T>C) in the general population?

MAFA p.His194= (c.582T>C) is common (popmax 99.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.582T>C · rs1872900 · VCV3059208

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 99.9%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

MAFA-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -3, phastCons 1
Overall
CADD	7.256	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 99.9% East Asian · 35,960/35,980 alleles

Filtering AF 99.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.7%

Overall 99.8% 1,488,098/1,490,592 alleles · common exomes 1,337,668/1,339,486 · genomes 150,430/151,106 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	100%	1
East Asiangrpmax	99.9%	1
Finnishnot grpmax-eligible	99.9%	1
Ashkenazi Jewishnot grpmax-eligible	99.9%	1
European (non-Finnish)	99.9%	1
Middle Eastern	99.8%	1
Remaining individualsnot grpmax-eligible	99.8%	1
South Asian	99.8%	1
Admixed American	99.7%	1
African / African-American	98.5%	1

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MAFA
Protein: p.His194=
Coding: c.582T>C
MANE Select: NM_201589
dbSNP: rs1872900
Type: single nucleotide variant
Location: chr8:143429825 (GRCh38)
Structure: AlphaFold pLDDT 64.06 · 1 PDB
Residue 194: the 'disordered' region

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

Disease context

MAFA-related disorder

Similar variants

MAFA c.*2C>T Likely benign same condition
MAFA p.Gly347Cys Benign same condition
MAFA p.Leu131= Benign same condition
MAFA p.Leu289= Likely benign same condition
MAFA p.Lys274= Benign same condition
MAFA p.Ala197_His203del Uncertain significance same condition
MAFA p.His207_His208del Benign same condition
MAFA p.Ala211Thr Uncertain significance ★★ ⚠ same type

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/mafa-p-his194 (accessed [today's date]).

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