Is SLC19A1 p.Phe212del (c.631TTC[1]) pathogenic?

SLC19A1 p.Phe212del (c.631TTC[1]) is classified Uncertain significance in SLC19A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-29). Ultra-rare (popmax 0.0109%, nfe); Associated with megaloblastic anemia, folate-responsive.

What condition is associated with SLC19A1 p.Phe212del (c.631TTC[1])?

SLC19A1 p.Phe212del (c.631TTC[1]) is associated with megaloblastic anemia, folate-responsive (ClinVar).

How common is SLC19A1 p.Phe212del (c.631TTC[1]) in the general population?

SLC19A1 p.Phe212del (c.631TTC[1]) is ultra-rare (popmax 0.0109%, nfe) (gnomAD).

SLC19A1 p.Phe212del

c.631TTC[1] · rs757838708 · VCV1054650

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, nfe)

Conditions

megaloblastic anemia, folate-responsive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP -0.52, phastCons 1
Overall
CADD	17.66	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0109% European (non-Finnish) · 129/1,179,746 alleles

Filtering AF 0.00936% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0088%

Overall 0.00992% 160/1,612,604 alleles · ultra-rare exomes 138/1,460,458 · genomes 22/152,146 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0913%	1,095
European (non-Finnish)grpmax	0.0109%	9,145
Remaining individualsnot grpmax-eligible	0.0048%	20,815
Admixed American	0.00167%	59,952

Ashkenazi Jewish 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: SLC19A1
Protein: p.Phe212del
Coding: c.631TTC[1]
MANE Select: NM_194255
dbSNP: rs757838708
Type: Microsatellite
Location: chr21:45531702 (GRCh38)
Gene constraint: LOEUF 1.585 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.30 · 19 PDB
Residue 212: a β-strand; a UniProt-annotated variant site (in megaf; loss of cellular uptake of folates, including methotrexate)

Full SLC19A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

megaloblastic anemia, folate-responsive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Megaloblastic anemia-immunodeficiency due to folate transporter 1 deficiency (Orphanet):

Onset: Infancy, Neonatal

Similar variants

SLC19A1 p.Phe212Leu Uncertain significance ★ ⚠ same residue
SLC19A1 p.Ser46Cys Uncertain significance ★★ ⚠ same condition
COL18A1 p.985GPP[5] Likely benign ★★ same type
RFC1 c.132+2923= Benign 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/slc19a1-p-phe212del (accessed [today's date]).

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