Is MTHFR p.Arg335Pro (c.1004G>C) pathogenic?

MTHFR p.Arg335Pro (c.1004G>C) is classified Uncertain significance in MTHFR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-28). AlphaMissense: likely pathogenic (0.8595); Very rare (popmax 0.0011%, sas); Associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency.

What condition is associated with MTHFR p.Arg335Pro (c.1004G>C)?

MTHFR p.Arg335Pro (c.1004G>C) is associated with homocystinuria due to methylene tetrahydrofolate reductase deficiency (ClinVar).

How common is MTHFR p.Arg335Pro (c.1004G>C) in the general population?

MTHFR p.Arg335Pro (c.1004G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MTHFR p.Arg335Pro (c.1004G>C)?

AlphaMissense predicts likely pathogenic (score 0.8595) — an in-silico prediction, not a clinical call.

MTHFR p.Arg335Pro

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.1004G>C · rs543016186 · VCV2747913

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8595 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

homocystinuria due to methylene tetrahydrofolate reductase deficiency

Computational evidence

Protein change
AlphaMissense	0.8595	likely pathogenic
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -12.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.48, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 12 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,082 alleles

Overall 6.2e-05% 1/1,613,074 alleles · very rare exomes 1/1,460,730 · genomes 0/152,344 · joint denominator

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.Arg335Pro
Coding: c.1004G>C
MANE Select: NM_005957
dbSNP: rs543016186
Type: single nucleotide variant
Location: chr1:11795125 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.13 · 4 PDB
Residue 335: an α-helix; a UniProt-annotated variant site (in mthfrd); a UniProt-annotated variant site (in mthfrd; reduced methylenetetrahydrofolate reductase activity; no effect on 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 p.Arg335Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MTHFR p.Arg335His Conflicting classifications of pathogenicity ★ ⚠ same residue
MTHFR p.Arg335Ser 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

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-arg335pro (accessed [today's date]).

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