Is MTHFR p.Phe64fs (c.191del) pathogenic?

MTHFR p.Phe64fs (c.191del) is classified Pathogenic in MTHFR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-03). Absent from gnomAD; Associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency.

What condition is associated with MTHFR p.Phe64fs (c.191del)?

MTHFR p.Phe64fs (c.191del) is associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency (ClinVar).

How common is MTHFR p.Phe64fs (c.191del) in the general population?

MTHFR p.Phe64fs (c.191del) is absent from gnomAD (gnomAD).

MTHFR p.Phe64fs

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.191del · rs2100577466 · VCV1070453

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.8	GERP 1.5, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MTHFR
Protein: p.Phe64fs
Coding: c.191del
MANE Select: NM_005957
dbSNP: rs2100577466
Type: Deletion
Location: chr1:11802926 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.13 · 4 PDB
Residue 64: a β-strand; a binding site

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 c.1167-2del Pathogenic ★★ same condition
MTHFR p.Asp38fs Likely pathogenic ★★ same condition
MTHFR p.Ile287fs Pathogenic/Likely pathogenic ★★ same condition
MTHFR p.Ile497fs Pathogenic/Likely pathogenic ★★ same condition
MTHFR p.Leu590fs Pathogenic ★★ same condition
MTHFR p.Ser410_Lys414del Pathogenic/Likely pathogenic ★★ same condition
MTHFR p.Lys215del Uncertain significance ★★ same condition
MTHFR c.1032-12_1038del 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-phe64fs (accessed [today's date]).

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