Is TAT p.Pro45Ser (c.133C>T) pathogenic?

TAT p.Pro45Ser (c.133C>T) is classified Benign in TAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.139); Low-frequency (popmax 2.3%, sas); Associated with tyrosinemia type II.

What condition is associated with TAT p.Pro45Ser (c.133C>T)?

TAT p.Pro45Ser (c.133C>T) is associated with tyrosinemia type II (ClinVar).

How common is TAT p.Pro45Ser (c.133C>T) in the general population?

TAT p.Pro45Ser (c.133C>T) is low-frequency (popmax 2.3%, sas) (gnomAD).

How is Tyrosinemia type 2 inherited?

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

What do computational predictors say about TAT p.Pro45Ser (c.133C>T)?

AlphaMissense predicts likely benign (score 0.139) — an in-silico prediction, not a clinical call.

TAT p.Pro45Ser

c.133C>T · rs575372249 · VCV320414

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.139 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.3%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tyrosinemia type II

Computational evidence

Protein change
AlphaMissense	0.139	likely benign
REVEL	0.247	benign-leaning
SaProt	LLR -7.76	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 4.2	GERP 1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,268 bp · p 0.051 · regional, not allelic
Overall
CADD	18.61	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.3% South Asian · 2,098/91,086 alleles

Filtering AF 2.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.19%

Overall 0.137% 2,213/1,614,172 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	2.3%	43
Remaining individualsnot grpmax-eligible	0.149%	672
Middle Eastern	0.099%	1,010
East Asian	0.00668%	14,962
Admixed American	0.00333%	30,003
African / African-American	0.00267%	37,522
European (non-Finnish)	0.000763%	131,115

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: TAT
Protein: p.Pro45Ser
Coding: c.133C>T
MANE Select: NM_000353
dbSNP: rs575372249
Type: single nucleotide variant
Location: chr16:71576283 (GRCh38)
Gene constraint: LOEUF 0.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.93 · 1 PDB

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

Disease context

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

For Tyrosinemia type 2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood, Infancy, Neonatal

Similar variants

TAT p.Pro45= Likely benign ★ same residue
TAT c.707-2A>G Pathogenic/Likely pathogenic ★★ same condition
TAT c.912+1G>A Likely pathogenic ★★ same condition
TAT p.Arg119Trp Pathogenic/Likely pathogenic ★★ same condition
TAT p.Arg297Ter Pathogenic/Likely pathogenic ★★ same condition
TAT p.Arg306Ter Pathogenic/Likely pathogenic ★★ same condition
TAT p.Arg417Gln Pathogenic/Likely pathogenic ★★ same condition
TAT p.Arg417Ter 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/tat-p-pro45ser (accessed [today's date]).

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