Is MTHFS p.Ser7fs (c.9_18dup) pathogenic?

MTHFS p.Ser7fs (c.918dup) is classified Likely pathogenic in MTHFS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-12). Associated with neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination.

MTHFS p.Ser7fs

Q: What condition is associated with MTHFS p.Ser7fs (c.9_18dup)?

MTHFS p.Ser7fs (c.9_18dup) is associated with neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (ClinVar).

Q: How is MTHFS-related developmental delay-microcephaly-short stature-epilepsy syndrome inherited?

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

c.9_18dup · VCV3775227

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination

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 1 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.48

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

Variant & gene context

Gene: MTHFS
Protein: p.Ser7fs
Coding: c.9_18dup
MANE Select: NM_006441
Type: Duplication
Location: chr15:79896970 (GRCh38)
Gene constraint: LOEUF 0.992 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 95.35 · 4 PDB
Residue 7: an α-helix

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

Disease context

neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MTHFS-related developmental delay-microcephaly-short stature-epilepsy syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

MTHFS p.Ala9fs Pathogenic ★★ same condition
MTHFS p.Gln162Ter Likely pathogenic ★ same condition
MTHFS p.Lys106Ter Pathogenic ★ same condition
MTHFS c.117+100C>G Uncertain significance ★ same condition
MTHFS p.Arg145Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
MTHFS p.Leu36Pro 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/mthfs-p-ser7fs (accessed [today's date]).

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