Is TCN2 p.Ser346Pro (c.1036T>C) pathogenic?

TCN2 p.Ser346Pro (c.1036T>C) is classified Uncertain significance in TCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-02). AlphaMissense: likely benign (0.0723); Absent from gnomAD v4.1.

How common is TCN2 p.Ser346Pro (c.1036T>C) in the general population?

TCN2 p.Ser346Pro (c.1036T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TCN2 p.Ser346Pro (c.1036T>C)?

AlphaMissense predicts likely benign (score 0.0723) — an in-silico prediction, not a clinical call.

TCN2 p.Ser346Pro

c.1036T>C · VCV4947400

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0723 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0723	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -7.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.5	GERP -3.2
Regional constraint	o/e 1.24	unconstrained · MANE · 19 kb · p 4e-08 · regional, not allelic
Overall
CADD	0.958	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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: TCN2
Protein: p.Ser346Pro
Coding: c.1036T>C
MANE Select: NM_000355
Type: single nucleotide variant
Location: chr22:30617425 (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 346: 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

Similar variants

TCN2 p.Ser346Phe Uncertain significance ★ ⚠ same residue
TCN2 p.Ser346= Likely benign ★ same residue
TCN2 c.1106+1G>A Pathogenic ★★ same type
TCN2 c.428-2A>G Pathogenic/Likely pathogenic ★★ same type
TCN2 p.Arg227Ter Pathogenic/Likely pathogenic ★★ same type
TCN2 p.Gln188Ter Pathogenic/Likely pathogenic ★★ same type
TCN2 p.Gln291Ter Pathogenic ★★ same type
TCN2 p.Gly367Ter Pathogenic/Likely pathogenic ★★ 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/tcn2-p-ser346pro (accessed [today's date]).

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