Is MMACHC p.Phe154= (c.462T>C) pathogenic?

MMACHC p.Phe154= (c.462T>C) is classified Likely benign in MMACHC (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.04%, amr); Associated with methylmalonic aciduria and homocystinuria type cblC.

What condition is associated with MMACHC p.Phe154= (c.462T>C)?

MMACHC p.Phe154= (c.462T>C) is associated with methylmalonic aciduria and homocystinuria type cblC (ClinVar).

How common is MMACHC p.Phe154= (c.462T>C) in the general population?

MMACHC p.Phe154= (c.462T>C) is ultra-rare (popmax 0.04%, amr) (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.

MMACHC p.Phe154=

c.462T>C · rs199747998 · VCV737924

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, amr)

Conditions

methylmalonic aciduria and homocystinuria type cblC

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.28	GERP 0.64, phastCons 0.44
Overall
CADD	5.453	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.04% Admixed American · 24/60,016 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.00211% 34/1,614,164 alleles · ultra-rare exomes 17/1,461,858 · genomes 17/152,306 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.04%	2,501
Remaining individualsnot grpmax-eligible	0.0128%	7,813
European (non-Finnish)	0.000169%	590,009

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.Phe154=
Coding: c.462T>C
MANE Select: NM_015506
dbSNP: rs199747998
Type: single nucleotide variant
Location: chr1:45508828 (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 154: a turn

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 p.Phe154Leu Uncertain significance ★★ ⚠ same residue
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

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-phe154 (accessed [today's date]).

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