Is MMACHC p.Ser245Pro (c.733T>C) pathogenic?

MMACHC p.Ser245Pro (c.733T>C) is classified Conflicting classifications of pathogenicity in MMACHC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-11-14). AlphaMissense: likely benign (0.0629); Ultra-rare (popmax 0.0147%, afr); Associated with methylmalonic aciduria and homocystinuria type cblC.

What condition is associated with MMACHC p.Ser245Pro (c.733T>C)?

MMACHC p.Ser245Pro (c.733T>C) is associated with methylmalonic aciduria and homocystinuria type cblC (ClinVar).

How common is MMACHC p.Ser245Pro (c.733T>C) in the general population?

MMACHC p.Ser245Pro (c.733T>C) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

How is Methylmalonic acidemia with homocystinuria inherited?

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

What do computational predictors say about MMACHC p.Ser245Pro (c.733T>C)?

AlphaMissense predicts likely benign (score 0.0629) — an in-silico prediction, not a clinical call.

MMACHC p.Ser245Pro

c.733T>C · rs779575471 · VCV949175

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0629 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methylmalonic aciduria and homocystinuria type cblC

Computational evidence

Protein change
AlphaMissense	0.0629	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.11	GERP -3.7
Regional constraint	o/e 1.08	unconstrained · MANE · 8,879 bp · p 0.15 · regional, not allelic
Overall
CADD	0.559	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 0.0147% African / African-American · 11/74,720 alleles

Filtering AF 0.00817% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00635%

Overall 0.000744% 12/1,612,280 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,793
Admixed American	0.00167%	59,798

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: MMACHC
Protein: p.Ser245Pro
Coding: c.733T>C
MANE Select: NM_015506
dbSNP: rs779575471
Type: single nucleotide variant
Location: chr1:45509099 (GRCh38)
Gene constraint: LOEUF 1.162 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.41 · 7 PDB
Residue 245: the 'disordered' region; a modified residue (phosphoserine)

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

Disease context

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

For Methylmalonic acidemia with homocystinuria (Orphanet):

Inheritance: Autosomal recessive, X-linked recessive
Onset: All ages

Similar variants

MMACHC c.430-1G>A Likely pathogenic ★★ same condition
MMACHC c.430-2A>G Likely pathogenic ★★ same condition
MMACHC c.81+1G>A Pathogenic ★★ same condition
MMACHC c.81+1G>C Pathogenic/Likely pathogenic ★★ same condition
MMACHC c.81+2T>G Pathogenic/Likely pathogenic ★★ same condition
MMACHC c.82-1G>A Pathogenic/Likely pathogenic ★★ same condition
MMACHC c.82-2A>G Pathogenic/Likely pathogenic ★★ same condition
MMACHC p.Ala117Pro 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/mmachc-p-ser245pro (accessed [today's date]).

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