Is TCN2 p.Ser46= (c.138C>T) pathogenic?

TCN2 p.Ser46= (c.138C>T) is classified Conflicting classifications of pathogenicity in TCN2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-01). Rare (popmax 0.448%, afr); Associated with transcobalamin II deficiency.

What condition is associated with TCN2 p.Ser46= (c.138C>T)?

TCN2 p.Ser46= (c.138C>T) is associated with transcobalamin II deficiency (ClinVar).

How common is TCN2 p.Ser46= (c.138C>T) in the general population?

TCN2 p.Ser46= (c.138C>T) is rare (popmax 0.448%, afr) (gnomAD).

How is Transcobalamin deficiency inherited?

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

TCN2 p.Ser46=

c.138C>T · rs143250551 · VCV341189

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.448%, afr)

Conditions

transcobalamin II 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 -0.23	GERP -4
Overall
CADD	5.086	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.448% African / African-American · 336/75,028 alleles

Filtering AF 0.408% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.393%

Overall 0.0261% 421/1,614,162 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.448%	223
Admixed American	0.0733%	1,364
Remaining individualsnot grpmax-eligible	0.0592%	1,689
European (non-Finnish)	0.000339%	295,008

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: TCN2
Protein: p.Ser46=
Coding: c.138C>T
MANE Select: NM_000355
dbSNP: rs143250551
Type: single nucleotide variant
Location: chr22:30610944 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.76 · 11 PDB
Residue 46: a disulfide bond

Full TCN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

transcobalamin II deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Transcobalamin deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TCN2 c.1106+1G>A Pathogenic ★★ same condition
TCN2 c.428-2A>G Pathogenic/Likely pathogenic ★★ same condition
TCN2 p.Arg227Ter Pathogenic/Likely pathogenic ★★ same condition
TCN2 p.Gln188Ter Pathogenic/Likely pathogenic ★★ same condition
TCN2 p.Gln291Ter Pathogenic ★★ same condition
TCN2 p.Gly367Ter Pathogenic/Likely pathogenic ★★ same condition
TCN2 c.753+5G>A Uncertain significance ★★ same condition
TCN2 p.Ala261Thr 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/tcn2-p-ser46 (accessed [today's date]).

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