Is TCN2 p.Pro40= (c.120T>C) pathogenic?

TCN2 p.Pro40= (c.120T>C) is classified Likely benign in TCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-09). Absent from gnomAD v4.1; Associated with transcobalamin II deficiency.

What condition is associated with TCN2 p.Pro40= (c.120T>C)?

TCN2 p.Pro40= (c.120T>C) is associated with transcobalamin II deficiency (ClinVar).

How common is TCN2 p.Pro40= (c.120T>C) in the general population?

TCN2 p.Pro40= (c.120T>C) is absent from gnomAD v4.1 (gnomAD).

How is Transcobalamin deficiency inherited?

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

TCN2 p.Pro40=

c.120T>C · rs2517900078 · VCV2759404

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 -0.03	GERP -3.9, phastCons 0.78
Overall
CADD	7.888	PHRED · no single calibrated threshold — expert panels disagree

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: TCN2
Protein: p.Pro40=
Coding: c.120T>C
MANE Select: NM_000355
dbSNP: rs2517900078
Type: single nucleotide variant
Location: chr22:30610926 (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 40: a disulfide bond; an α-helix

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 p.Pro40fs Pathogenic ★ same residue
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

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-pro40 (accessed [today's date]).

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