Is MTHFR p.Phe435= (c.1305C>T) pathogenic?

MTHFR p.Phe435= (c.1305C>T) is classified Benign in MTHFR (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele; Associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency.

What condition is associated with MTHFR p.Phe435= (c.1305C>T)?

MTHFR p.Phe435= (c.1305C>T) is associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency (ClinVar).

MTHFR p.Phe435=

Q: How common is MTHFR p.Phe435= (c.1305C>T) in the general population?

MTHFR p.Phe435= (c.1305C>T) is common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1305C>T · rs4846051 · VCV167306

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Common

common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.52	GERP -3.1
Overall
CADD	1.95	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 100% East Asian · 44,818/44,838 alleles

Filtering AF 99.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.7%

Overall 98.2% 1,585,600/1,613,924 alleles · common exomes 1,447,325/1,461,860 · genomes 138,275/152,064 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	100%	1
East Asiangrpmax	100%	1
South Asian	99.9%	1
European (non-Finnish)	99.9%	1
Amishnot grpmax-eligible	99.6%	1
Ashkenazi Jewishnot grpmax-eligible	98.7%	1
Middle Eastern	98.2%	1
Remaining individualsnot grpmax-eligible	97.6%	1
Admixed American	97.5%	1
African / African-American	68.6%	1

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe435=
Coding: c.1305C>T
MANE Select: NM_005957
dbSNP: rs4846051
Type: single nucleotide variant
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.Phe435fs Pathogenic ★ same residue
MTHFR p.Phe435Ser 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

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-phe435 (accessed [today's date]).

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