Is MTHFR p.Phe435fs (c.1304_1305del) pathogenic?

MTHFR p.Phe435fs (c.13041305del) is classified Pathogenic in MTHFR (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-28). Very rare (popmax 8.47e-05%, nfe); Associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency.

What condition is associated with MTHFR p.Phe435fs (c.1304_1305del)?

MTHFR p.Phe435fs (c.1304_1305del) is associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency (ClinVar).

How common is MTHFR p.Phe435fs (c.1304_1305del) in the general population?

MTHFR p.Phe435fs (c.1304_1305del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

MTHFR p.Phe435fs

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.1304_1305del · rs756018487 · VCV1072666

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, 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.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.2	GERP 1.5, phastCons 0.092
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,002 alleles

Overall 0.000658% 1/152,076 alleles · very rare

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.Phe435fs
Coding: c.1304_1305del
MANE Select: NM_005957
dbSNP: rs756018487
Type: Deletion
Location: chr1:11794400 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.13 · 4 PDB
Residue 435: an α-helix; a UniProt-annotated variant site (in mthfrd)

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.Phe435= Benign ★★ same residue
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

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-phe435fs (accessed [today's date]).

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