Is TH p.Asp413His (c.1237G>C) pathogenic?

TH p.Asp413His (c.1237G>C) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-23). AlphaMissense: likely benign (0.1899); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with TH p.Asp413His (c.1237G>C)?

TH p.Asp413His (c.1237G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TH p.Asp413His (c.1237G>C) in the general population?

TH p.Asp413His (c.1237G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TH p.Asp413His (c.1237G>C)?

AlphaMissense predicts likely benign (score 0.1899) — an in-silico prediction, not a clinical call.

TH p.Asp413His

c.1237G>C · VCV3968254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1899 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1899	likely benign
REVEL	0.763	pathogenic-leaning
SaProt	LLR -11.38	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	24.5	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 D444H vs ClinVar D413H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,004 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00143% 23/1,612,098 alleles · very rare exomes 21/1,459,958 · genomes 2/152,140 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,235
Admixed Americangrpmax	0.00167%	60,004
European (non-Finnish)	0.00161%	62,105
South Asian	0.0011%	91,056

Remaining individuals 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.Asp413His
Coding: c.1237G>C
MANE Select: NM_000360
Type: single nucleotide variant
Location: chr11:2165329 (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

Similar variants

TH p.Asp413= Likely benign ★ same residue
TH p.Asp413Asn Benign ★ same residue
TH p.Tyr224Ter Pathogenic ★★ same condition
TH c.91-853C>T Uncertain significance ★★ ⚠ same condition
TH c.91-892C>T Uncertain significance ★★ ⚠ same condition
TH p.Ala210Ser Uncertain significance ★★ ⚠ same condition
TH p.Ala317Gly Uncertain significance ★★ ⚠ same condition
TH p.Ala492Val Uncertain significance ★★ ⚠ 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-asp413his (accessed [today's date]).

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