Is MMAA p.Pro151fs (c.450dup) pathogenic?

MMAA p.Pro151fs (c.450dup) is classified Pathogenic in MMAA (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-01-24). Very rare (popmax 0.00356%, nfe); Associated with methylmalonic aciduria, cblA type.

What condition is associated with MMAA p.Pro151fs (c.450dup)?

MMAA p.Pro151fs (c.450dup) is associated with methylmalonic aciduria, cblA type, methylmalonic acidemia (ClinVar).

How common is MMAA p.Pro151fs (c.450dup) in the general population?

MMAA p.Pro151fs (c.450dup) is very rare (popmax 0.00356%, nfe) (gnomAD).

How is Vitamin B12-responsive methylmalonic acidemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

MMAA p.Pro151fs

c.450dup · rs754973022 · VCV551182

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Conditions

methylmalonic aciduria, cblA type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.15	phastCons 0.99
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00356% European (non-Finnish) · 42/1,180,002 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00266% 43/1,613,934 alleles · very rare exomes 40/1,461,686 · genomes 3/152,248 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,095
African / African-American	0.00133%	74,946

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: MMAA
Protein: p.Pro151fs
Coding: c.450dup
MANE Select: NM_172250
dbSNP: rs754973022
Type: Duplication
Location: chr4:145642370 (GRCh38)
Gene constraint: LOEUF 1.156 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.71 · 2 PDB
Residue 151: a UniProt-annotated variant site (in maca); a binding site

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

Disease context

methylmalonic aciduria, cblA type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: methylmalonic acidemia

For Vitamin B12-responsive methylmalonic acidemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

MMAA p.Pro151= Likely benign ★ same residue
MMAA p.Pro151Leu Uncertain significance ⚠ same residue
MMAA p.Cys184fs Pathogenic ★★ same condition
MMAA p.Gly218fs Pathogenic ★★ same condition
MMAA p.Asp237Ter Likely pathogenic ★ same condition
MMAA p.Asp255fs Likely pathogenic ★ same condition
MMAA p.Asp255Ter Pathogenic ★ same condition
MMAA p.Leu148fs Pathogenic ★ 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/mmaa-p-pro151fs (accessed [today's date]).

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