Is MTHFD1 p.Asp259= (c.777C>T) pathogenic?

MTHFD1 p.Asp259= (c.777C>T) is classified Likely benign in MTHFD1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-06-01). Rare (popmax 0.182%, sas).

How common is MTHFD1 p.Asp259= (c.777C>T) in the general population?

MTHFD1 p.Asp259= (c.777C>T) is rare (popmax 0.182%, sas) (gnomAD).

MTHFD1 p.Asp259=

c.777C>T · rs138933024 · VCV740197

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.182%, sas)

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 -11	GERP -4.6
Overall
CADD	4.488	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.182% South Asian · 166/91,068 alleles

Filtering AF 0.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.151%

Overall 0.0273% 441/1,613,974 alleles · rare exomes 366/1,461,826 · genomes 75/152,148 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.989%	101
South Asiangrpmax	0.182%	549
African / African-American	0.0895%	1,118
Middle Eastern	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.0288%	3,471
Finnishnot grpmax-eligible	0.0172%	5,821
East Asian	0.0134%	7,482
European (non-Finnish)	0.0133%	7,516
Admixed American	0.00667%	14,994
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp259=
Coding: c.777C>T
MANE Select: NM_005956
dbSNP: rs138933024
Type: single nucleotide variant
Location: chr14:64424853 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 94.63 · 12 PDB
Residue 259: a UniProt-annotated variant site (in cimah); the 'methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase (d/c) domain' region; an α-helix

Full MTHFD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MTHFD1 p.Asp259His Uncertain significance ★ ⚠ same residue
MTHFD1 c.727+1G>A Pathogenic/Likely pathogenic ★★ same type
MTHFD1 p.Arg173Cys Pathogenic/Likely pathogenic ★★ same type
MTHFD1 p.Gln100Ter Likely pathogenic ★★ same type
MTHFD1 p.Glu225Ter Pathogenic ★★ same type
MTHFD1 p.Ser49Phe Pathogenic/Likely pathogenic ★★ same type
MTHFD1 c.186+5C>T Uncertain significance ★★ same type
MTHFD1 p.Arg173His Uncertain significance ★★ ⚠ same type

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-asp259 (accessed [today's date]).

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