What condition is associated with MTHFR p.Pro39= (c.117C>T)?

MTHFR p.Pro39= (c.117C>T) is associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency (ClinVar).

MTHFR p.Pro39=

Q: Is MTHFR p.Pro39= (c.117C>T) pathogenic?

MTHFR p.Pro39= (c.117C>T) is classified Benign in MTHFR (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 14.4%, sas) — too common for a highly-penetrant pathogenic allele; Associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency.

Q: How common is MTHFR p.Pro39= (c.117C>T) in the general population?

MTHFR p.Pro39= (c.117C>T) is common (popmax 14.4%, sas) — 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.117C>T · rs2066470 · VCV292246

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 14.4%, sas) — 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 -15	GERP -3
Overall
CADD	0.195	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 14.4% South Asian · 13,075/91,050 alleles

Filtering AF 14.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.1%

Overall 10.2% 165,154/1,613,948 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	14.4%	7
Finnishnot grpmax-eligible	11.4%	9
East Asian	11.1%	9
European (non-Finnish)	10.4%	10
Remaining individualsnot grpmax-eligible	10.3%	10
African / African-American	7.79%	13
Admixed American	6.29%	16
Amishnot grpmax-eligible	4.82%	21
Middle Eastern	4.34%	23
Ashkenazi Jewishnot grpmax-eligible	3.4%	29

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.Pro39=
Coding: c.117C>T
MANE Select: NM_005957
dbSNP: rs2066470
Type: single nucleotide variant
Location: chr1:11803000 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.13 · 4 PDB
Residue 39: the 'disordered' region

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.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
MTHFR c.1752+1G>T 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-pro39 (accessed [today's date]).

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