Is MTHFR p.Ser494= (c.1482C>T) pathogenic?

MTHFR p.Ser494= (c.1482C>T) is classified Likely benign in MTHFR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-30). Ultra-rare (popmax 0.0379%, eas); Associated with Inborn genetic diseases.

What condition is associated with MTHFR p.Ser494= (c.1482C>T)?

MTHFR p.Ser494= (c.1482C>T) is associated with Inborn genetic diseases, homocystinuria due to methylene tetrahydrofolate reductase deficiency (ClinVar).

How common is MTHFR p.Ser494= (c.1482C>T) in the general population?

MTHFR p.Ser494= (c.1482C>T) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

MTHFR p.Ser494=

c.1482C>T · rs765736104 · VCV1147860

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -2.4
Overall
CADD	0.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0379% East Asian · 17/44,882 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0031% 50/1,613,718 alleles · ultra-rare exomes 47/1,461,476 · genomes 3/152,242 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0379%	2,640
Middle Eastern	0.0165%	6,078
South Asian	0.00878%	11,384
African / African-American	0.00267%	37,476
European (non-Finnish)	0.00178%	56,183
Remaining individualsnot grpmax-eligible	0.0016%	62,466

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.Ser494=
Coding: c.1482C>T
MANE Select: NM_005957
dbSNP: rs765736104
Type: single nucleotide variant
Location: chr1:11793955 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.13 · 4 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: homocystinuria due to methylene tetrahydrofolate reductase deficiency

Similar variants

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
MTHFR c.1752+1G>T 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-ser494 (accessed [today's date]).

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