Is MTHFR p.Phe236= (c.708C>T) pathogenic?

MTHFR p.Phe236= (c.708C>T) is classified Conflicting classifications of pathogenicity in MTHFR (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-31). Rare (popmax 0.38%, afr); Associated with Inborn genetic diseases.

What condition is associated with MTHFR p.Phe236= (c.708C>T)?

MTHFR p.Phe236= (c.708C>T) is associated with Inborn genetic diseases, homocystinuria due to methylene tetrahydrofolate reductase deficiency (ClinVar).

How common is MTHFR p.Phe236= (c.708C>T) in the general population?

MTHFR p.Phe236= (c.708C>T) is rare (popmax 0.38%, afr) (gnomAD).

MTHFR p.Phe236=

c.708C>T · rs34279942 · VCV287120

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.38%, 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 4.3	GERP 1.5, phastCons 1
Overall
CADD	9.443	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.38% African / African-American · 285/75,074 alleles

Filtering AF 0.343% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.329%

Overall 0.0403% 650/1,614,220 alleles · rare exomes 455/1,461,860 · genomes 195/152,360 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.38%	263
Ashkenazi Jewishnot grpmax-eligible	0.324%	308
Middle Eastern	0.099%	1,010
Remaining individualsnot grpmax-eligible	0.0864%	1,158
Admixed American	0.065%	1,539
European (non-Finnish)	0.0142%	7,024
South Asian	0.0022%	45,543

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.Phe236=
Coding: c.708C>T
MANE Select: NM_005957
dbSNP: rs34279942
Type: single nucleotide variant
Location: chr1:11796278 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.13 · 4 PDB
Residue 236: an α-helix

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.Phe236Leu Uncertain significance ★ ⚠ same residue
MTHFR p.Phe236Ser 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

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-phe236 (accessed [today's date]).

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