Is MMAB p.Asp123fs (c.367del) pathogenic?

MMAB p.Asp123fs (c.367del) is classified Pathogenic in MMAB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-03). Very rare (popmax 0.00195%, nfe); Associated with methylmalonic aciduria, cblB type.

What condition is associated with MMAB p.Asp123fs (c.367del)?

MMAB p.Asp123fs (c.367del) is associated with methylmalonic aciduria, cblB type, methylmalonic acidemia (ClinVar).

How common is MMAB p.Asp123fs (c.367del) in the general population?

MMAB p.Asp123fs (c.367del) is very rare (popmax 0.00195%, nfe) (gnomAD).

How is Vitamin B12-responsive methylmalonic acidemia inherited?

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

MMAB p.Asp123fs

c.367del · rs1387128853 · VCV1173993

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Conditions

methylmalonic aciduria, cblB 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 5 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Overall
CADD	33.0	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 0.00195% European (non-Finnish) · 23/1,176,834 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00143% 23/1,607,690 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: MMAB
Protein: p.Asp123fs
Coding: c.367del
MANE Select: NM_052845
dbSNP: rs1387128853
Type: Deletion
Location: chr12:109561834 (GRCh38)
Gene constraint: LOEUF 0.874 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.39 · 6 PDB
Residue 123: an α-helix

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

Disease context

methylmalonic aciduria, cblB 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

MMAB p.Asp123Asn Uncertain significance ★ ⚠ same residue
MMAB p.Asp123= Likely benign ★ same residue
MMAB p.Ala192fs Pathogenic/Likely pathogenic ★★ same condition
MMAB p.Tyr219fs Pathogenic ★★ same condition
MMAB p.Val188_Ala192del Pathogenic/Likely pathogenic ★★ same condition
MMAB p.Arg191fs Likely pathogenic ★ same condition
MMAB p.Arg76fs Likely pathogenic ★ same condition
MMAB p.Cys189fs 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/mmab-p-asp123fs (accessed [today's date]).

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