Is TYR p.Phe134Ser (c.401T>C) pathogenic?

TYR p.Phe134Ser (c.401T>C) is classified Uncertain significance in TYR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-25). AlphaMissense: likely pathogenic (0.9318); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TYR p.Phe134Ser (c.401T>C)?

TYR p.Phe134Ser (c.401T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TYR p.Phe134Ser (c.401T>C) in the general population?

TYR p.Phe134Ser (c.401T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TYR p.Phe134Ser (c.401T>C)?

AlphaMissense predicts likely pathogenic (score 0.9318) — an in-silico prediction, not a clinical call.

TYR p.Phe134Ser

c.401T>C · rs33955261 · VCV3185252

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9318 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9318	likely pathogenic · top 9% in TYR
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -13.95	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 117 kb · p 0.00089 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: TYR
Protein: p.Phe134Ser
Coding: c.401T>C
MANE Select: NM_000372
dbSNP: rs33955261
Type: single nucleotide variant
Location: chr11:89178354 (GRCh38)
Gene constraint: LOEUF 1.346 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.79 · 1 PDB
Residue 134: a UniProt-annotated variant site (in)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TYR p.Phe134Leu Uncertain significance ★ ⚠ same residue
TYR p.Arg298Gln Uncertain significance ★★ ⚠ same condition
TYR p.Arg405Cys Uncertain significance ★★ ⚠ same condition
TYR p.Asn230Lys Uncertain significance ★★ ⚠ same condition
TYR p.Asp169Asn Uncertain significance ★★ ⚠ same condition
TYR p.Glu281Gly Uncertain significance ★★ ⚠ same condition
TYR p.Leu140Ser Uncertain significance ★★ ⚠ same condition
TYR p.Met426Thr Uncertain significance ★★ ⚠ 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/tyr-p-phe134ser (accessed [today's date]).

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