MTHFR p.Pro35=
c.105G>A · rs368987205 · VCV1779939
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.0033%, sas)
Conditions
1
Inborn genetic diseases
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.44 | acceptor gain · deltas |
|---|---|---|
| Pangolin | Δ0.20 | gain · loss 0.00 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP -11 | GERP -3 |
| Overall | ||
| CADD | 1.854 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0033%
South Asian · 3/91,032 alleles
Filtering AF
0.000875%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000443%
Overall
0.000342%
5/1,461,776 alleles · very rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0033% | 30,344 |
| European (non-Finnish) | 0.000169% | 589,998 |
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.Pro35=
- Coding
- c.105G>A
- MANE Select
- NM_005957
- dbSNP
- rs368987205
- Type
- single nucleotide variant
- Location
- chr1:11803012 (GRCh38)
- Gene constraint
- LOEUF 0.859 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 89.13 · 4 PDB
- Residue 35
- the 'disordered' region
Similar variants
- MTHFR p.Ala524Glu Uncertain significance ★★ ⚠ same condition
- MTHFR p.Ala650Val Uncertain significance ★★ ⚠ same condition
- MTHFR p.Arg535Pro Uncertain significance ★★ ⚠ same condition
- MTHFR p.Arg606His Uncertain significance ★★ ⚠ same condition
- MTHFR p.Asp629Gly Uncertain significance ★★ ⚠ same condition
- MTHFR p.Gln267Lys Uncertain significance ★★ same condition
- MTHFR p.Gly36Val Uncertain significance ★★ ⚠ same condition
- MTHFR p.Gly87Asp 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/mthfr-p-pro35 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown