Is MTHFD1 p.Phe294Ser (c.881T>C) pathogenic?

MTHFD1 p.Phe294Ser (c.881T>C) is classified Uncertain significance in MTHFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-20). AlphaMissense: likely benign (0.2239); Absent from gnomAD v4.1; Associated with combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia.

How common is MTHFD1 p.Phe294Ser (c.881T>C) in the general population?

MTHFD1 p.Phe294Ser (c.881T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MTHFD1 p.Phe294Ser (c.881T>C)?

AlphaMissense predicts likely benign (score 0.2239) — an in-silico prediction, not a clinical call.

MTHFD1 p.Phe294Ser

Q: What condition is associated with MTHFD1 p.Phe294Ser (c.881T>C)?

MTHFD1 p.Phe294Ser (c.881T>C) is associated with combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (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.881T>C · rs2550501114 · VCV2433814

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2239 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

Computational evidence

Protein change
AlphaMissense	0.2239	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 0.88, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 39 kb · p 0.00013 · regional, not allelic
Overall
CADD	18.99	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

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.Phe294Ser
Coding: c.881T>C
MANE Select: NM_005956
dbSNP: rs2550501114
Type: single nucleotide variant
Location: chr14:64425755 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 94.63 · 12 PDB
Residue 294: a UniProt-annotated variant site (in cimah); an α-helix

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

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

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

MTHFD1 p.Phe294Val Uncertain significance ★ ⚠ same residue
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.Ser49Phe Pathogenic/Likely pathogenic ★★ same condition
MTHFD1 p.Arg366Trp Uncertain significance ★★ ⚠ same condition
MTHFD1 p.Ile391Val 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/mthfd1-p-phe294ser (accessed [today's date]).

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