Is TH p.Glu43Lys (c.127G>A) pathogenic?

TH p.Glu43Lys (c.127G>A) is classified Uncertain significance in TH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-29). AlphaMissense: ambiguous (0.3743); Ultra-rare (popmax 0.035%, amr); Associated with Inborn genetic diseases.

What condition is associated with TH p.Glu43Lys (c.127G>A)?

TH p.Glu43Lys (c.127G>A) is associated with Inborn genetic diseases, TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Glu43Lys (c.127G>A) in the general population?

TH p.Glu43Lys (c.127G>A) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about TH p.Glu43Lys (c.127G>A)?

AlphaMissense predicts ambiguous (score 0.3743) — an in-silico prediction, not a clinical call.

TH p.Glu43Lys

c.127G>A · rs772029518 · VCV968339

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3743 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3743	ambiguous
REVEL	0.553	indeterminate
SaProt	LLR -8.93	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 0.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	24.1	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 E74K vs ClinVar E43K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.035% Admixed American · 21/59,944 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0115% 186/1,610,580 alleles · ultra-rare exomes 172/1,458,394 · genomes 14/152,186 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,854
European (non-Finnish)	0.0136%	7,373
Remaining individualsnot grpmax-eligible	0.00482%	20,743
African / African-American	0.00267%	37,439

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.Glu43Lys
Coding: c.127G>A
MANE Select: NM_000360
dbSNP: rs772029518
Type: single nucleotide variant
Location: chr11:2169835 (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-glu43lys (accessed [today's date]).

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