Is MMAB p.Phe83Ser (c.248T>C) pathogenic?

MMAB p.Phe83Ser (c.248T>C) is classified Uncertain significance in MMAB (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely pathogenic (0.9309); Very rare (popmax 0.00133%, afr); Associated with methylmalonic aciduria, cblB type.

What condition is associated with MMAB p.Phe83Ser (c.248T>C)?

MMAB p.Phe83Ser (c.248T>C) is associated with methylmalonic aciduria, cblB type (ClinVar).

How common is MMAB p.Phe83Ser (c.248T>C) in the general population?

MMAB p.Phe83Ser (c.248T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Vitamin B12-responsive methylmalonic acidemia inherited?

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

What do computational predictors say about MMAB p.Phe83Ser (c.248T>C)?

AlphaMissense predicts likely pathogenic (score 0.9309) — an in-silico prediction, not a clinical call.

MMAB p.Phe83Ser

c.248T>C · rs1185132313 · VCV1007490

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9309 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methylmalonic aciduria, cblB type

Computational evidence

Protein change
AlphaMissense	0.9309	likely pathogenic · top 5% in MMAB
REVEL	0.975	strongly pathogenic-leaning
SaProt	LLR -11.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.26 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,070 alleles

Overall 6.19e-05% 1/1,614,262 alleles · very rare exomes 1/1,461,876 · genomes 0/152,386 · joint denominator

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.Phe83Ser
Coding: c.248T>C
MANE Select: NM_052845
dbSNP: rs1185132313
Type: single nucleotide variant
Location: chr12:109568812 (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 83: 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

For Vitamin B12-responsive methylmalonic acidemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

MMAB p.Phe83Leu Uncertain significance ★ ⚠ same residue
MMAB c.197-1G>T Pathogenic ★★ same condition
MMAB c.290+1G>A Likely pathogenic ★★ same condition
MMAB c.291-1G>A Pathogenic ★★ same condition
MMAB c.349-1G>C Pathogenic/Likely pathogenic ★★ same condition
MMAB c.584+2T>C Likely pathogenic ★★ same condition
MMAB p.Arg186Gln Pathogenic/Likely pathogenic ★★ same condition
MMAB p.Arg186Pro Likely 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-phe83ser (accessed [today's date]).

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