Is MTHFR p.Ile91= (c.273A>C) pathogenic?

MTHFR p.Ile91= (c.273A>C) is classified Likely benign in MTHFR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-19). Very rare (popmax 0.000169%, nfe); Associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency.

What condition is associated with MTHFR p.Ile91= (c.273A>C)?

MTHFR p.Ile91= (c.273A>C) is associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency (ClinVar).

How common is MTHFR p.Ile91= (c.273A>C) in the general population?

MTHFR p.Ile91= (c.273A>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

MTHFR p.Ile91=

Q: How is Homocystinuria due to methylene tetrahydrofolate reductase deficiency inherited?

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

c.273A>C · rs2522960307 · VCV2810948

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

homocystinuria due to methylene tetrahydrofolate reductase deficiency

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 -0.72	GERP -3, phastCons 0.019
Overall
CADD	7.226	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,030 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,146 alleles · very rare exomes 2/1,461,886 · genomes 0/152,260 · joint denominator

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.Ile91=
Coding: c.273A>C
MANE Select: NM_005957
dbSNP: rs2522960307
Type: single nucleotide variant
Location: chr1:11801363 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.13 · 4 PDB
Residue 91: a β-strand

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

Disease context

homocystinuria due to methylene tetrahydrofolate reductase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Homocystinuria due to methylene tetrahydrofolate reductase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

MTHFR p.Ile91Val Uncertain significance ★★ ⚠ 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-ile91 (accessed [today's date]).

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