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

TYR p.Pro45Ser (c.133C>T) is classified Uncertain significance in TYR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-15). AlphaMissense: likely benign (0.0922); Very rare (popmax 0.00167%, amr).

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

TYR p.Pro45Ser (c.133C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

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

AlphaMissense predicts likely benign (score 0.0922) — an in-silico prediction, not a clinical call.

TYR p.Pro45Ser

c.133C>T · rs13312739 · VCV2135013

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0922 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0922	likely benign
REVEL	0.478	indeterminate
SaProt	LLR -7.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 117 kb · p 0.00089 · regional, not allelic
Overall
CADD	21.6	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

Grpmax group 0.00167% Admixed American · 1/60,020 alleles

Overall 0.000124% 2/1,614,160 alleles · very rare exomes 2/1,461,878 · genomes 0/152,282 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,020
European (non-Finnish)	8.47e-05%	1,180,026

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: TYR
Protein: p.Pro45Ser
Coding: c.133C>T
MANE Select: NM_000372
dbSNP: rs13312739
Type: single nucleotide variant
Location: chr11:89178086 (GRCh38)
Gene constraint: LOEUF 1.346 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.79 · 1 PDB

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

Similar variants

TYR p.Pro45Thr Likely pathogenic ★★ ⚠ same residue
TYR p.Pro45Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TYR c.1036+1G>A Pathogenic/Likely pathogenic ★★ same type
TYR c.1036+2T>G Pathogenic ★★ same type
TYR c.1037-1G>A Pathogenic/Likely pathogenic ★★ same type
TYR c.1037-2A>G Pathogenic/Likely pathogenic ★★ same type
TYR c.1037-3C>G Pathogenic/Likely pathogenic ★★ same type
TYR c.1037-7T>A 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/tyr-p-pro45ser (accessed [today's date]).

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