Is MTHFD1 p.Pro73Arg (c.218C>G) pathogenic?

MTHFD1 p.Pro73Arg (c.218C>G) is classified Uncertain significance in MTHFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-22). AlphaMissense: likely benign (0.3175); Absent from gnomAD v4.1.

How common is MTHFD1 p.Pro73Arg (c.218C>G) in the general population?

MTHFD1 p.Pro73Arg (c.218C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MTHFD1 p.Pro73Arg (c.218C>G)?

AlphaMissense predicts likely benign (score 0.3175) — an in-silico prediction, not a clinical call.

MTHFD1 p.Pro73Arg

c.218C>G · rs75108146 · VCV1931581

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3175 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3175	likely benign
REVEL	0.449	indeterminate
SaProt	LLR -13.75	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 39 kb · p 0.00013 · 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

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: MTHFD1
Protein: p.Pro73Arg
Coding: c.218C>G
MANE Select: NM_005956
dbSNP: rs75108146
Type: single nucleotide variant
Location: chr14:64412503 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 94.63 · 12 PDB
Residue 73: the 'methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase (d/c) domain' region

Full MTHFD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MTHFD1 c.727+1G>A Pathogenic/Likely pathogenic ★★ same type
MTHFD1 p.Arg173Cys Pathogenic/Likely pathogenic ★★ same type
MTHFD1 p.Gln100Ter Likely pathogenic ★★ same type
MTHFD1 p.Glu225Ter Pathogenic ★★ same type
MTHFD1 p.Ser49Phe Pathogenic/Likely pathogenic ★★ same type
MTHFD1 c.186+5C>T Uncertain significance ★★ same type
MTHFD1 p.Arg173His Uncertain significance ★★ ⚠ same type
MTHFD1 p.Arg293Cys Uncertain significance ★★ ⚠ same type

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/mthfd1-p-pro73arg (accessed [today's date]).

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