Is FOLR1 p.Pro49= (c.147C>T) pathogenic?

FOLR1 p.Pro49= (c.147C>T) is classified Likely benign in FOLR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). Very rare (popmax 0.00223%, eas); Associated with neurodegenerative syndrome due to cerebral folate transport deficiency.

What condition is associated with FOLR1 p.Pro49= (c.147C>T)?

FOLR1 p.Pro49= (c.147C>T) is associated with neurodegenerative syndrome due to cerebral folate transport deficiency (ClinVar).

How common is FOLR1 p.Pro49= (c.147C>T) in the general population?

FOLR1 p.Pro49= (c.147C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

FOLR1 p.Pro49=

Q: How is Neurodegenerative syndrome due to cerebral folate transport deficiency inherited?

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

c.147C>T · rs758121091 · VCV761181

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

neurodegenerative syndrome due to cerebral folate transport deficiency

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 -3.2
Overall
CADD	0.123	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,892 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00062% 10/1,613,920 alleles · very rare exomes 7/1,461,832 · genomes 3/152,088 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,892
Remaining individualsnot grpmax-eligible	0.0016%	62,468
African / African-American	0.00134%	74,890
European (non-Finnish)	0.000593%	168,574

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: FOLR1
Protein: p.Pro49=
Coding: c.147C>T
MANE Select: NM_016729
dbSNP: rs758121091
Type: single nucleotide variant
Location: chr11:72192320 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 5 PDB
Residue 49: a β-strand

Full FOLR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodegenerative syndrome due to cerebral folate transport deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Neurodegenerative syndrome due to cerebral folate transport deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

FOLR1 p.Arg125Cys Pathogenic/Likely pathogenic ★★ same condition
FOLR1 p.Gln118Ter Pathogenic ★★ same condition
FOLR1 p.Ala226Val Uncertain significance ★★ ⚠ same condition
FOLR1 p.Ala22Val Uncertain significance ★★ ⚠ same condition
FOLR1 p.Arg125His Uncertain significance ★★ ⚠ same condition
FOLR1 p.Arg128Gln Uncertain significance ★★ ⚠ same condition
FOLR1 p.Arg147Cys Uncertain significance ★★ ⚠ same condition
FOLR1 p.Asn201Tyr 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/folr1-p-pro49 (accessed [today's date]).

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