Is TH p.His330Arg (c.989A>G) pathogenic?

TH p.His330Arg (c.989A>G) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-14). AlphaMissense: likely pathogenic (0.9929); No allele count reported in gnomAD v4.1 (AN 1,602,680).

How common is TH p.His330Arg (c.989A>G) in the general population?

TH p.His330Arg (c.989A>G) is no allele count reported in gnomAD v4.1 (AN 1,602,680) (gnomAD).

What do computational predictors say about TH p.His330Arg (c.989A>G)?

AlphaMissense predicts likely pathogenic (score 0.9929) — an in-silico prediction, not a clinical call.

TH p.His330Arg

c.989A>G · VCV3895648

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9929 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,602,680)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9929	likely pathogenic · top 6% in TH
REVEL	0.963	strongly pathogenic-leaning
SaProt	LLR -12.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	28.6	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 H361R vs ClinVar H330R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,602,680). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TH
Protein: p.His330Arg
Coding: c.989A>G
MANE Select: NM_000360
Type: single nucleotide variant
Location: chr11:2166538 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 361 UniProt numbering: a binding site

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

Similar variants

TH p.His330Gln Uncertain significance ★ ⚠ same residue
TH p.His330= Likely benign ★ same residue
TH p.His330fs Pathogenic ★ same residue
TH c.1200+2T>C Likely pathogenic ★★ same type
TH c.1334+1G>A Likely pathogenic ★★ same type
TH c.312+1G>A Likely pathogenic ★★ same type
TH c.488-1G>A Pathogenic ★★ same type
TH c.644+1G>A 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/th-p-his330arg (accessed [today's date]).

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