Is TAT p.Pro15Ser (c.43C>T) pathogenic?

TAT p.Pro15Ser (c.43C>T) is classified Benign in TAT (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0772); Common (popmax 18.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with tyrosinemia type II.

What condition is associated with TAT p.Pro15Ser (c.43C>T)?

TAT p.Pro15Ser (c.43C>T) is associated with tyrosinemia type II (ClinVar).

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.Pro15Ser (c.43C>T)?

AlphaMissense predicts likely benign (score 0.0772) — an in-silico prediction, not a clinical call.

TAT p.Pro15Ser

Q: How common is TAT p.Pro15Ser (c.43C>T) in the general population?

TAT p.Pro15Ser (c.43C>T) is common (popmax 18.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.43C>T · rs74344827 · VCV320415

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0772 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 18.7%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tyrosinemia type II

Computational evidence

Protein change
AlphaMissense	0.0772	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -5.42	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 2.3	GERP 1, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 8,268 bp · p 0.051 · regional, not allelic
Overall
CADD	8.494	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 18.7% African / African-American · 14,051/74,940 alleles

Filtering AF 18.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.4%

Overall 16% 258,839/1,613,932 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	19.4%	5
African / African-Americangrpmax	18.7%	5
South Asian	18%	6
European (non-Finnish)	16.4%	6
Remaining individualsnot grpmax-eligible	16.1%	6
Middle Eastern	13.5%	7
Ashkenazi Jewishnot grpmax-eligible	13.4%	7
Admixed American	10.2%	10
Amishnot grpmax-eligible	8.79%	11
East Asian	3.76%	27

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro15Ser
Coding: c.43C>T
MANE Select: NM_000353
dbSNP: rs74344827
Type: single nucleotide variant
Location: chr16:71576373 (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 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
TAT p.Arg57Ter 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-pro15ser (accessed [today's date]).

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