Is TCN2 p.Pro341= (c.1023G>A) pathogenic?

TCN2 p.Pro341= (c.1023G>A) is classified Benign/Likely benign in TCN2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Low-frequency (popmax 3.64%, nfe); Associated with transcobalamin II deficiency.

What condition is associated with TCN2 p.Pro341= (c.1023G>A)?

TCN2 p.Pro341= (c.1023G>A) is associated with transcobalamin II deficiency (ClinVar).

How common is TCN2 p.Pro341= (c.1023G>A) in the general population?

TCN2 p.Pro341= (c.1023G>A) is low-frequency (popmax 3.64%, nfe) (gnomAD).

How is Transcobalamin deficiency inherited?

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

TCN2 p.Pro341=

c.1023G>A · rs76802001 · VCV341210

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.64%, nfe)

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 -2.4	GERP -3.3
Overall
CADD	0.229	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.64% European (non-Finnish) · 42,912/1,179,996 alleles

Filtering AF 3.61% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.6%

Overall 3.12% 50,305/1,614,028 alleles · low-frequency exomes 46,561/1,461,870 · genomes 3,744/152,158 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	3.64%	27
Middle Eastern	3.58%	28
Admixed American	3.34%	30
Remaining individualsnot grpmax-eligible	3.13%	32
Finnishnot grpmax-eligible	2.21%	45
Ashkenazi Jewishnot grpmax-eligible	1.32%	76
Amishnot grpmax-eligible	1.21%	83
South Asian	0.977%	102
African / African-American	0.661%	151
East Asian	0.0156%	6,411

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.Pro341=
Coding: c.1023G>A
MANE Select: NM_000355
dbSNP: rs76802001
Type: single nucleotide variant
Location: chr22:30617412 (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 341: a UniProt-annotated variant site (in tcn2d; likely pathogenic); a β-strand

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.Pro341Ala Uncertain significance ★★ ⚠ same residue
TCN2 p.Pro341Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TCN2 p.Pro341Thr Uncertain significance ★ ⚠ 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

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-pro341 (accessed [today's date]).

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