Is MTHFR p.Ala587= (c.1761C>T) pathogenic?

MTHFR p.Ala587= (c.1761C>T) is classified Conflicting classifications of pathogenicity in MTHFR (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-09). Rare (popmax 0.224%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MTHFR p.Ala587= (c.1761C>T)?

MTHFR p.Ala587= (c.1761C>T) is associated with Inborn genetic diseases, homocystinuria due to methylene tetrahydrofolate reductase deficiency (ClinVar).

How common is MTHFR p.Ala587= (c.1761C>T) in the general population?

MTHFR p.Ala587= (c.1761C>T) is rare (popmax 0.224%, nfe) (gnomAD).

MTHFR p.Ala587=

c.1761C>T · rs115049252 · VCV292232

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.224%, nfe)

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 5.2	GERP -0.92, phastCons 1
Overall
CADD	8.036	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.224% European (non-Finnish) · 2,638/1,179,852 alleles

Filtering AF 0.216% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.214%

Overall 0.194% 3,134/1,613,444 alleles · rare exomes 2,912/1,461,832 · genomes 222/151,612 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.224%	447
Remaining individualsnot grpmax-eligible	0.2%	500
Admixed American	0.18%	555
South Asian	0.163%	615
Finnishnot grpmax-eligible	0.144%	696
African / African-American	0.0281%	3,556
Middle Eastern	0.0165%	6,062
East Asian	0.00223%	44,806

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.Ala587=
Coding: c.1761C>T
MANE Select: NM_005957
dbSNP: rs115049252
Type: single nucleotide variant
Location: chr1:11790890 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.13 · 4 PDB
Residue 587: 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.Ala587Gly 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
MTHFR c.1632+2T>G 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-ala587 (accessed [today's date]).

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