Is TH p.Val155Met (c.463G>A) pathogenic?

TH p.Val155Met (c.463G>A) is classified Uncertain significance in TH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-24). AlphaMissense: likely benign (0.2502); Ultra-rare (popmax 0.0128%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TH p.Val155Met (c.463G>A)?

TH p.Val155Met (c.463G>A) is associated with Inborn genetic diseases, TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Val155Met (c.463G>A) in the general population?

TH p.Val155Met (c.463G>A) is ultra-rare (popmax 0.0128%, nfe) (gnomAD).

What do computational predictors say about TH p.Val155Met (c.463G>A)?

AlphaMissense predicts likely benign (score 0.2502) — an in-silico prediction, not a clinical call.

TH p.Val155Met

c.463G>A · rs145023516 · VCV2040097

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2502 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0128%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2502	likely benign
REVEL	0.466	indeterminate
SaProt	LLR -10.59	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 2.7	GERP -2.2, phastCons 0.99
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	23.8	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 V186M vs ClinVar V155M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0128% European (non-Finnish) · 151/1,179,848 alleles

Filtering AF 0.0111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0105%

Overall 0.01% 162/1,612,346 alleles · ultra-rare exomes 144/1,460,094 · genomes 18/152,252 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.548%	182
European (non-Finnish)grpmax	0.0128%	7,814
Remaining individualsnot grpmax-eligible	0.0032%	31,219
East Asian	0.00223%	44,840
South Asian	0.0022%	45,532
Admixed American	0.00167%	60,014

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val155Met
Coding: c.463G>A
MANE Select: NM_000360
dbSNP: rs145023516
Type: single nucleotide variant
Location: chr11:2168515 (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 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
TH c.90+13G>A 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-val155met (accessed [today's date]).

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