Is MAFA p.Ala154= (c.462G>C) pathogenic?

MAFA p.Ala154= (c.462G>C) is classified Likely benign in MAFA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-01). Ultra-rare (popmax 0.0385%, sas).

How common is MAFA p.Ala154= (c.462G>C) in the general population?

MAFA p.Ala154= (c.462G>C) is ultra-rare (popmax 0.0385%, sas) (gnomAD).

MAFA p.Ala154=

c.462G>C · VCV4534125

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0385%, sas)

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 -0.59	GERP -2.7, phastCons 0.1
Overall
CADD	9.103	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0385% South Asian · 15/38,974 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0191%

Overall 0.00144% 18/1,254,218 alleles · ultra-rare exomes 16/1,109,368 · genomes 2/144,850 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0385%	2,598
Remaining individualsnot grpmax-eligible	0.00658%	15,193

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.Ala154=
Coding: c.462G>C
MANE Select: NM_201589
Type: single nucleotide variant
Location: chr8:143429945 (GRCh38)
Structure: AlphaFold pLDDT 64.06 · 1 PDB

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

Similar variants

MAFA p.Ala211Thr Uncertain significance ★★ ⚠ same type
MAFA p.Arg333Trp Uncertain significance ★★ ⚠ same type
MAFA p.Arg44His Uncertain significance ★★ same type
MAFA p.Ser64Phe Likely pathogenic ★ same type
MAFA p.Thr57Arg Pathogenic ★ same type
MAFA p.Ala138Glu Uncertain significance ★ ⚠ same type
MAFA p.Ala158Glu Uncertain significance ★ ⚠ same type
MAFA p.Ala159Val 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-ala154 (accessed [today's date]).

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