Is TH p.Val468Met (c.1402G>A) pathogenic?

TH p.Val468Met (c.1402G>A) is classified Conflicting classifications of pathogenicity in TH (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.1609); Rare (popmax 0.268%, eas); Associated with Inborn genetic diseases.

What condition is associated with TH p.Val468Met (c.1402G>A)?

TH p.Val468Met (c.1402G>A) is associated with Inborn genetic diseases, TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Val468Met (c.1402G>A) in the general population?

TH p.Val468Met (c.1402G>A) is rare (popmax 0.268%, eas) (gnomAD).

What do computational predictors say about TH p.Val468Met (c.1402G>A)?

AlphaMissense predicts likely benign (score 0.1609) — an in-silico prediction, not a clinical call.

TH p.Val468Met

c.1402G>A · rs1800033 · VCV412030

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1609 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.268%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1609	likely benign
REVEL	0.594	indeterminate
SaProt	LLR -11.18	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -0.93, phastCons 0.99
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V499M vs ClinVar V468M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.268% East Asian · 112/41,818 alleles

Filtering AF 0.228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.212%

Overall 0.00857% 132/1,539,918 alleles · rare exomes 123/1,387,598 · genomes 9/152,320 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.268%	373
Admixed American	0.0175%	5,715
Remaining individualsnot grpmax-eligible	0.00506%	19,758
South Asian	0.00122%	81,960
European (non-Finnish)	0.000614%	162,809

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.Val468Met
Coding: c.1402G>A
MANE Select: NM_000360
dbSNP: rs1800033
Type: single nucleotide variant
Location: chr11:2164325 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 499 UniProt numbering: a UniProt-annotated variant site (in); a β-strand

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.Val468= Likely benign ★ 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
TH c.90+10C>T Pathogenic/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-val468met (accessed [today's date]).

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