Is MTHFD1 p.Arg366Trp (c.1096C>T) pathogenic?

MTHFD1 p.Arg366Trp (c.1096C>T) is classified Uncertain significance in MTHFD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-11). AlphaMissense: likely benign (0.0956); Ultra-rare (popmax 0.0317%, amr); Associated with combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia.

How common is MTHFD1 p.Arg366Trp (c.1096C>T) in the general population?

MTHFD1 p.Arg366Trp (c.1096C>T) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

What do computational predictors say about MTHFD1 p.Arg366Trp (c.1096C>T)?

AlphaMissense predicts likely benign (score 0.0956) — an in-silico prediction, not a clinical call.

MTHFD1 p.Arg366Trp

Q: What condition is associated with MTHFD1 p.Arg366Trp (c.1096C>T)?

MTHFD1 p.Arg366Trp (c.1096C>T) 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.1096C>T · rs139612806 · VCV1367539

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0956 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

Computational evidence

Protein change
AlphaMissense	0.0956	likely benign
REVEL	0.262	benign-leaning
SaProt	LLR -12.66	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 39 kb · p 0.00013 · regional, not allelic
Overall
CADD	28.3	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

Grpmax group 0.0317% Admixed American · 19/59,988 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00458% 74/1,613,960 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,157
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,700
Middle Eastern	0.0165%	6,076
African / African-American	0.0147%	6,807
Remaining individualsnot grpmax-eligible	0.0064%	15,620
European (non-Finnish)	0.00237%	42,144
East Asian	0.00223%	44,894
South Asian	0.0022%	45,540

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: MTHFD1
Protein: p.Arg366Trp
Coding: c.1096C>T
MANE Select: NM_005956
dbSNP: rs139612806
Type: single nucleotide variant
Location: chr14:64426161 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 94.63 · 12 PDB
Residue 366: a UniProt-annotated variant site (in cimah); the 'formyltetrahydrofolate synthetase domain' region

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

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MTHFD1 p.Glu225Ter Pathogenic ★★ same condition
MTHFD1 p.Ser49Phe Pathogenic/Likely pathogenic ★★ same condition
MTHFD1 p.Ile391Val Uncertain significance ★★ ⚠ same condition
MTHFD1 p.Ile464Val Uncertain significance ★★ ⚠ same condition
MTHFD1 p.Ile862Val 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-arg366trp (accessed [today's date]).

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