Is MMAA p.Ser79Pro (c.235T>C) pathogenic?

MMAA p.Ser79Pro (c.235T>C) is classified Likely pathogenic in MMAA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.1585); Ultra-rare (popmax 0.0132%, sas); Associated with methylmalonic aciduria, cblA type.

What condition is associated with MMAA p.Ser79Pro (c.235T>C)?

MMAA p.Ser79Pro (c.235T>C) is associated with methylmalonic aciduria, cblA type (ClinVar).

How common is MMAA p.Ser79Pro (c.235T>C) in the general population?

MMAA p.Ser79Pro (c.235T>C) is ultra-rare (popmax 0.0132%, sas) (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 MMAA p.Ser79Pro (c.235T>C)?

AlphaMissense predicts likely benign (score 0.1585) — an in-silico prediction, not a clinical call.

MMAA p.Ser79Pro

c.235T>C · VCV4852883

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1585 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

methylmalonic aciduria, cblA type

Computational evidence

Protein change
AlphaMissense	0.1585	likely benign ⚠ discordant with ClinVar
REVEL	0.467	indeterminate
SaProt	LLR -10.14	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 16 kb · p 0.11 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% South Asian · 12/91,090 alleles

Filtering AF 0.0075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.000805% 13/1,614,080 alleles · ultra-rare exomes 12/1,461,876 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,591
East Asian	0.00223%	44,888

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.Ser79Pro
Coding: c.235T>C
MANE Select: NM_172250
Type: single nucleotide variant
Location: chr4:145639374 (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 79: a UniProt-annotated variant site (in maca)

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

For Vitamin B12-responsive methylmalonic acidemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

MMAA c.440-2A>G Likely pathogenic ★★ same condition
MMAA c.562+2T>C Likely pathogenic ★★ same condition
MMAA c.733+1G>A Pathogenic/Likely pathogenic ★★ same condition
MMAA c.733+1G>T Pathogenic/Likely pathogenic ★★ same condition
MMAA c.820-1G>A Pathogenic/Likely pathogenic ★★ same condition
MMAA c.820-1G>C Pathogenic/Likely pathogenic ★★ same condition
MMAA c.820-2A>G Likely pathogenic ★★ same condition
MMAA p.Arg145Gln Pathogenic/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/mmaa-p-ser79pro (accessed [today's date]).

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