Is MTHFR p.Val536Phe (c.1606G>T) pathogenic?

MTHFR p.Val536Phe (c.1606G>T) is classified Conflicting classifications of pathogenicity in MTHFR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-11). AlphaMissense: likely pathogenic (0.8523); Very rare (popmax 0.00186%, nfe); Associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency.

What condition is associated with MTHFR p.Val536Phe (c.1606G>T)?

MTHFR p.Val536Phe (c.1606G>T) is associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency (ClinVar).

How common is MTHFR p.Val536Phe (c.1606G>T) in the general population?

MTHFR p.Val536Phe (c.1606G>T) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about MTHFR p.Val536Phe (c.1606G>T)?

AlphaMissense predicts likely pathogenic (score 0.8523) — an in-silico prediction, not a clinical call.

MTHFR p.Val536Phe

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.1606G>T · rs786204028 · VCV187896

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8523 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

homocystinuria due to methylene tetrahydrofolate reductase deficiency

Computational evidence

Protein change
AlphaMissense	0.8523	likely pathogenic
REVEL	0.537	indeterminate
SaProt	LLR -11.09	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 12 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00186% European (non-Finnish) · 22/1,180,018 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00136% 22/1,614,076 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.Val536Phe
Coding: c.1606G>T
MANE Select: NM_005957
dbSNP: rs786204028
Type: single nucleotide variant
Location: chr1:11792304 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.13 · 4 PDB
Residue 536: a β-strand; a UniProt-annotated variant site (in mthfrd; reduced methylenetetrahydrofolate reductase activity; reduced affinity for nadph)

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-val536phe (accessed [today's date]).

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