Is SLC19A1 p.Ser46Cys (c.136A>T) pathogenic?

SLC19A1 p.Ser46Cys (c.136A>T) is classified Uncertain significance in SLC19A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-03). AlphaMissense: ambiguous (0.5543); Absent from gnomAD v4.1; Associated with megaloblastic anemia, folate-responsive.

What condition is associated with SLC19A1 p.Ser46Cys (c.136A>T)?

SLC19A1 p.Ser46Cys (c.136A>T) is associated with megaloblastic anemia, folate-responsive (ClinVar).

How common is SLC19A1 p.Ser46Cys (c.136A>T) in the general population?

SLC19A1 p.Ser46Cys (c.136A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SLC19A1 p.Ser46Cys (c.136A>T)?

AlphaMissense predicts ambiguous (score 0.5543) — an in-silico prediction, not a clinical call.

SLC19A1 p.Ser46Cys

c.136A>T · rs2078177014 · VCV2798991

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5543 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

megaloblastic anemia, folate-responsive

Computational evidence

Protein change
AlphaMissense	0.5543	ambiguous
REVEL	0.847	moderately pathogenic-leaning
SaProt	LLR -10.61	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP -2.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.89 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SLC19A1
Protein: p.Ser46Cys
Coding: c.136A>T
MANE Select: NM_194255
dbSNP: rs2078177014
Type: single nucleotide variant
Location: chr21:45537824 (GRCh38)
Gene constraint: LOEUF 1.585 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.30 · 19 PDB
Residue 46: a β-strand

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.Phe212del Uncertain significance ★★ same condition
COL18A1 p.Arg1081Ter Pathogenic/Likely pathogenic ★★ same type
COL18A1 p.Arg915Ter Pathogenic/Likely pathogenic ★★ same type
RFC1 p.Arg383Ter Pathogenic/Likely pathogenic ★★ same type
COL18A1 c.*30G>A Uncertain significance ★★ same type
COL18A1 p.Ala1089Thr Uncertain significance ★★ ⚠ same type
COL18A1 p.Ala1254Val Uncertain significance ★★ ⚠ same type
COL18A1 p.Arg1081Gln 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/slc19a1-p-ser46cys (accessed [today's date]).

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