Is TH p.Val81Met (c.241G>A) pathogenic?

TH p.Val81Met (c.241G>A) is classified Benign/Likely benign in TH (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0952); Common (popmax 74.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with schizophrenia.

What condition is associated with TH p.Val81Met (c.241G>A)?

TH p.Val81Met (c.241G>A) is associated with schizophrenia, TH-deficient dopa-responsive dystonia (ClinVar).

What do computational predictors say about TH p.Val81Met (c.241G>A)?

AlphaMissense predicts likely benign (score 0.0952) — an in-silico prediction, not a clinical call.

TH p.Val81Met

Q: How common is TH p.Val81Met (c.241G>A) in the general population?

TH p.Val81Met (c.241G>A) is common (popmax 74.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.241G>A · rs6356 · VCV21866

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

AlphaMissense

likely benign

0.0952 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 74.8%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

schizophrenia

Computational evidence

Protein change
AlphaMissense	0.0952	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	LLR -8.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3	GERP -1.4
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	1.135	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 V112M vs ClinVar V81M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 74.8% East Asian · 33,520/44,838 alleles

Filtering AF 74.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 73.8%

Overall 38.1% 615,084/1,612,890 alleles · common exomes 564,672/1,460,814 · genomes 50,412/152,076 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	74.8%	1
South Asian	55.1%	2
Middle Eastern	47.5%	2
Finnishnot grpmax-eligible	44.6%	2
Admixed American	41.4%	2
Remaining individualsnot grpmax-eligible	40.4%	2
Ashkenazi Jewishnot grpmax-eligible	39%	3
European (non-Finnish)	36.3%	3
Amishnot grpmax-eligible	24.3%	4
African / African-American	13.9%	7

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.Val81Met
Coding: c.241G>A
MANE Select: NM_000360
dbSNP: rs6356
Type: single nucleotide variant
Location: chr11:2169721 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 112 UniProt numbering: a UniProt-annotated variant site (in)

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

Disease context

schizophrenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: TH-deficient dopa-responsive dystonia

Similar variants

TH p.Val81fs Pathogenic ★ 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-val81met (accessed [today's date]).

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