Is MTHFR p.Pro343Arg (c.1028C>G) pathogenic?

MTHFR p.Pro343Arg (c.1028C>G) is classified Uncertain significance in MTHFR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-10). AlphaMissense: likely benign (0.1495); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with MTHFR p.Pro343Arg (c.1028C>G)?

MTHFR p.Pro343Arg (c.1028C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MTHFR p.Pro343Arg (c.1028C>G) in the general population?

MTHFR p.Pro343Arg (c.1028C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MTHFR p.Pro343Arg (c.1028C>G)?

AlphaMissense predicts likely benign (score 0.1495) — an in-silico prediction, not a clinical call.

MTHFR p.Pro343Arg

c.1028C>G · VCV3875415

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1495 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1495	likely benign
REVEL	0.67	pathogenic-leaning
SaProt	LLR -3.26	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 12 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	25.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MTHFR
Protein: p.Pro343Arg
Coding: c.1028C>G
MANE Select: NM_005957
Type: single nucleotide variant
Location: chr1:11795101 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.13 · 4 PDB

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

Similar variants

MTHFR p.Pro343Ser Uncertain significance ★★ ⚠ same residue
MTHFR p.Pro343Leu Uncertain significance ★ ⚠ same residue
MTHFR p.Pro343= Likely benign ★ same residue
MTHFR p.Ala524Glu Uncertain significance ★★ ⚠ same condition
MTHFR p.Ala650Val Uncertain significance ★★ ⚠ same condition
MTHFR p.Arg535Pro Uncertain significance ★★ ⚠ same condition
MTHFR p.Arg606His Uncertain significance ★★ ⚠ same condition
MTHFR p.Asp629Gly Uncertain significance ★★ ⚠ 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-pro343arg (accessed [today's date]).

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