Is TH p.His215= (c.645C>T) pathogenic?

TH p.His215= (c.645C>T) is classified Conflicting classifications of pathogenicity in TH (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-04-27). Rare (popmax 0.416%, mid); Associated with Inborn genetic diseases.

What condition is associated with TH p.His215= (c.645C>T)?

TH p.His215= (c.645C>T) is associated with Inborn genetic diseases, TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.His215= (c.645C>T) in the general population?

TH p.His215= (c.645C>T) is rare (popmax 0.416%, mid) (gnomAD).

TH p.His215=

c.645C>T · rs768037080 · VCV284674

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.416%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.007	strongly benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -8.4	GERP -2.5
Overall
CADD	0.016	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.416% Middle Eastern · 25/6,016 alleles

Filtering AF 0.289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.247%

Overall 0.00443% 69/1,558,432 alleles · rare exomes 60/1,406,268 · genomes 9/152,164 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.416%	241
African / African-American	0.0176%	5,667
Remaining individualsnot grpmax-eligible	0.00663%	15,092
South Asian	0.00236%	42,338
European (non-Finnish)	0.00208%	47,969
Finnishnot grpmax-eligible	0.0017%	58,720

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: TH
Protein: p.His215=
Coding: c.645C>T
MANE Select: NM_000360
dbSNP: rs768037080
Type: single nucleotide variant
Location: chr11:2167485 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB

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

Also linked: TH-deficient dopa-responsive dystonia

Similar variants

TH p.His215Tyr Likely pathogenic ★ ⚠ same residue
TH p.His215Gln Uncertain significance ★ ⚠ same residue
TH c.1200+2T>C Likely pathogenic ★★ same condition
TH c.1334+1G>A Likely pathogenic ★★ same condition
TH c.312+1G>A Likely pathogenic ★★ same condition
TH c.488-1G>A Pathogenic ★★ same condition
TH c.644+1G>A Likely pathogenic ★★ same condition
TH c.695+1G>C Likely 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/th-p-his215 (accessed [today's date]).

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