Is TH p.Cys248Ser (c.743G>C) pathogenic?

TH p.Cys248Ser (c.743G>C) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.7982); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TH p.Cys248Ser (c.743G>C)?

TH p.Cys248Ser (c.743G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TH p.Cys248Ser (c.743G>C) in the general population?

TH p.Cys248Ser (c.743G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TH p.Cys248Ser (c.743G>C)?

AlphaMissense predicts likely pathogenic (score 0.7982) — an in-silico prediction, not a clinical call.

TH p.Cys248Ser

c.743G>C · VCV4633100

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7982 · 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	0.7982	likely pathogenic
REVEL	0.956	strongly pathogenic-leaning
SaProt	LLR -10.20	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 7.3	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	26.1	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM C279S vs ClinVar C248S) — verify the residue.

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: TH
Protein: p.Cys248Ser
Coding: c.743G>C
MANE Select: NM_000360
Type: single nucleotide variant
Location: chr11:2166985 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 279 UniProt numbering: a UniProt-annotated variant site (in arsegs)

Full TH 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

TH p.Cys248= Likely benign ★ same residue
TH p.Tyr224Ter Pathogenic ★★ same condition
TH c.91-853C>T Uncertain significance ★★ ⚠ same condition
TH c.91-892C>T Uncertain significance ★★ ⚠ same condition
TH p.Ala210Ser Uncertain significance ★★ ⚠ same condition
TH p.Ala317Gly Uncertain significance ★★ ⚠ same condition
TH p.Ala492Val Uncertain significance ★★ ⚠ same condition
TH p.Ala56Val 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/th-p-cys248ser (accessed [today's date]).

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