Is MTHFR p.Phe435Ser (c.1304T>C) pathogenic?

MTHFR p.Phe435Ser (c.1304T>C) is classified Likely pathogenic in MTHFR (ClinVar, Single submitter, 2 submitters; last evaluated 2023-04-27). AlphaMissense: likely pathogenic (0.9102); Very rare (popmax 0.000508%, nfe); Associated with neural tube defects, folate-sensitive.

What condition is associated with MTHFR p.Phe435Ser (c.1304T>C)?

MTHFR p.Phe435Ser (c.1304T>C) is associated with neural tube defects, folate-sensitive (ClinVar).

How common is MTHFR p.Phe435Ser (c.1304T>C) in the general population?

MTHFR p.Phe435Ser (c.1304T>C) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about MTHFR p.Phe435Ser (c.1304T>C)?

AlphaMissense predicts likely pathogenic (score 0.9102) — an in-silico prediction, not a clinical call.

MTHFR p.Phe435Ser

c.1304T>C · rs754015864 · VCV2676849

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9102 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neural tube defects, folate-sensitive

Computational evidence

Protein change
AlphaMissense	0.9102	likely pathogenic ✓ concordant with ClinVar
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -14.66	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 12 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	24.8	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 0.000508% European (non-Finnish) · 6/1,179,992 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,858 alleles · very rare

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: MTHFR
Protein: p.Phe435Ser
Coding: c.1304T>C
MANE Select: NM_005957
dbSNP: rs754015864
Type: single nucleotide variant
Location: chr1:11794401 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.13 · 4 PDB
Residue 435: an α-helix; a UniProt-annotated variant site (in mthfrd)

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

Disease context

neural tube defects, folate-sensitive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MTHFR p.Phe435= Benign ★★ same residue
MTHFR c.1166+1G>T Likely pathogenic ★★ same condition
MTHFR c.1166+5G>C Pathogenic/Likely pathogenic ★★ same condition
MTHFR c.1347+1G>A Pathogenic ★★ same condition
MTHFR c.1348-1G>C Likely pathogenic ★★ same condition
MTHFR c.1530+1G>A Likely pathogenic ★★ same condition
MTHFR c.1530+1G>T Likely pathogenic ★★ same condition
MTHFR c.1632+2T>G 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/mthfr-p-phe435ser (accessed [today's date]).

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