Is MTHFR p.Asp92= (c.276C>T) pathogenic?

MTHFR p.Asp92= (c.276C>T) is classified Benign/Likely benign in MTHFR (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). Rare (popmax 0.769%, afr); Associated with Inborn genetic diseases.

What condition is associated with MTHFR p.Asp92= (c.276C>T)?

MTHFR p.Asp92= (c.276C>T) is associated with Inborn genetic diseases, homocystinuria due to methylene tetrahydrofolate reductase deficiency (ClinVar).

How common is MTHFR p.Asp92= (c.276C>T) in the general population?

MTHFR p.Asp92= (c.276C>T) is rare (popmax 0.769%, afr) (gnomAD).

MTHFR p.Asp92=

c.276C>T · rs45546035 · VCV196430

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.769%, afr)

Conditions

Inborn genetic diseases

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 0.33	GERP -2.9, phastCons 0.61
Overall
CADD	11.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.769% African / African-American · 577/75,052 alleles

Filtering AF 0.717% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.696%

Overall 0.0382% 616/1,614,190 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.769%	130
Remaining individualsnot grpmax-eligible	0.016%	6,251
Admixed American	0.015%	6,669
European (non-Finnish)	0.00161%	62,107
Finnishnot grpmax-eligible	0.00156%	64,040

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: MTHFR
Protein: p.Asp92=
Coding: c.276C>T
MANE Select: NM_005957
dbSNP: rs45546035
Type: single nucleotide variant
Location: chr1:11801360 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.13 · 4 PDB
Residue 92: a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: homocystinuria due to methylene tetrahydrofolate reductase deficiency

Similar variants

MTHFR p.Asp92fs Pathogenic/Likely pathogenic ★★ same residue
MTHFR c.1166+1G>T Likely pathogenic ★★ same condition
MTHFR c.1166+5G>C Pathogenic/Likely pathogenic ★★ same condition
MTHFR c.1347+1G>A Pathogenic ★★ same condition
MTHFR c.1348-1G>C Likely pathogenic ★★ same condition
MTHFR c.1530+1G>A Likely pathogenic ★★ same condition
MTHFR c.1530+1G>T Likely pathogenic ★★ same condition
MTHFR c.1632+2T>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/mthfr-p-asp92 (accessed [today's date]).

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