Is MMADHC p.Phe204= (c.612C>T) pathogenic?

MMADHC p.Phe204= (c.612C>T) is classified Likely benign in MMADHC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-11). Very rare (popmax 0.00336%, sas); Associated with methylmalonic aciduria and homocystinuria type cblD.

What condition is associated with MMADHC p.Phe204= (c.612C>T)?

MMADHC p.Phe204= (c.612C>T) is associated with methylmalonic aciduria and homocystinuria type cblD (ClinVar).

How common is MMADHC p.Phe204= (c.612C>T) in the general population?

MMADHC p.Phe204= (c.612C>T) is very rare (popmax 0.00336%, sas) (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.

MMADHC p.Phe204=

c.612C>T · rs1573874420 · VCV712887

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00336%, sas)

Conditions

methylmalonic aciduria and homocystinuria type cblD

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -0.83, phastCons 1
Overall
CADD	7.326	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00336% South Asian · 3/89,216 alleles

Filtering AF 0.000893% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000448%

Overall 0.00025% 4/1,600,504 alleles · very rare exomes 4/1,448,226 · genomes 0/152,278 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00336%	29,739
Remaining individualsnot grpmax-eligible	0.00161%	61,956

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: MMADHC
Protein: p.Phe204=
Coding: c.612C>T
MANE Select: NM_015702
dbSNP: rs1573874420
Type: single nucleotide variant
Location: chr2:149571169 (GRCh38)
Gene constraint: LOEUF 0.986 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.67 · 4 PDB
Residue 204: an α-helix; a UniProt-annotated variant site (in macd); a UniProt-annotated variant site (in mahcd)

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

Disease context

methylmalonic aciduria and homocystinuria type cblD — 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

MMADHC c.10-1G>A Pathogenic/Likely pathogenic ★★ same condition
MMADHC c.10-1G>C Likely pathogenic ★★ same condition
MMADHC c.154+1G>A Pathogenic/Likely pathogenic ★★ same condition
MMADHC c.610-1G>A Likely pathogenic ★★ same condition
MMADHC p.Arg158Ter Pathogenic ★★ same condition
MMADHC p.Arg216Ter Pathogenic/Likely pathogenic ★★ same condition
MMADHC p.Arg250Ter Pathogenic/Likely pathogenic ★★ same condition
MMADHC p.Gln180Ter 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/mmadhc-p-phe204 (accessed [today's date]).

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