Is MTHFD1 p.Asp244fs (c.731dup) pathogenic?

MTHFD1 p.Asp244fs (c.731dup) is classified Likely pathogenic in MTHFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-14). Associated with combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia.

MTHFD1 p.Asp244fs

Q: What condition is associated with MTHFD1 p.Asp244fs (c.731dup)?

MTHFD1 p.Asp244fs (c.731dup) is associated with combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia, neural tube defects, folate-sensitive (ClinVar).

Q: How is Combined immunodeficiency-megaloblastic anemia due to methylenetetrahydrofolate dehydrogenase 1 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.731dup · VCV3576656

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 28
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.21	GERP -4.2

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: MTHFD1
Protein: p.Asp244fs
Coding: c.731dup
MANE Select: NM_005956
Type: Duplication
Location: chr14:64424806 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 94.63 · 12 PDB
Residue 244: a UniProt-annotated variant site (in cimah); the 'methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase (d/c) domain' region; a β-strand

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

Disease context

combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neural tube defects, folate-sensitive

For Combined immunodeficiency-megaloblastic anemia due to methylenetetrahydrofolate dehydrogenase 1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

MTHFD1 p.Ile85fs Likely pathogenic ★ same condition
MTHFD1 p.Asp244Tyr Uncertain significance ★ ⚠ same residue
MTHFD1 p.Met615fs Uncertain significance ★ same condition
MTHFD1 c.727+1G>A Pathogenic/Likely pathogenic ★★ same condition
MTHFD1 p.Arg173Cys Pathogenic/Likely pathogenic ★★ same condition
MTHFD1 p.Gln100Ter Likely pathogenic ★★ same condition
MTHFD1 p.Glu225Ter Pathogenic ★★ same condition
MTHFD1 p.Ile53fs 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/mthfd1-p-asp244fs (accessed [today's date]).

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