Is TCN2 p.Pro307= (c.921A>C) pathogenic?

TCN2 p.Pro307= (c.921A>C) is classified Conflicting classifications of pathogenicity in TCN2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-02). Rare (popmax 0.214%, mid); Associated with transcobalamin II deficiency.

What condition is associated with TCN2 p.Pro307= (c.921A>C)?

TCN2 p.Pro307= (c.921A>C) is associated with transcobalamin II deficiency (ClinVar).

How common is TCN2 p.Pro307= (c.921A>C) in the general population?

TCN2 p.Pro307= (c.921A>C) is rare (popmax 0.214%, mid) (gnomAD).

How is Transcobalamin deficiency inherited?

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

TCN2 p.Pro307=

c.921A>C · rs138738105 · VCV341206

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.214%, mid)

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 3.3	GERP 1.1, phastCons 1
Overall
CADD	8.475	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.214% Middle Eastern · 13/6,062 alleles

Filtering AF 0.187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.178%

Overall 0.0294% 474/1,614,210 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.214%	466
South Asian	0.212%	472
Remaining individualsnot grpmax-eligible	0.0464%	2,156
Admixed American	0.0217%	4,617
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,935
European (non-Finnish)	0.0185%	5,413
Finnishnot grpmax-eligible	0.00156%	64,042
African / African-American	0.00133%	75,054

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.Pro307=
Coding: c.921A>C
MANE Select: NM_000355
dbSNP: rs138738105
Type: single nucleotide variant
Location: chr22:30615768 (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 307: a UniProt-annotated variant site (in tcn2d; likely pathogenic)

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-pro307 (accessed [today's date]).

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