Is TH p.Glu69Gln (c.205G>C) pathogenic?

TH p.Glu69Gln (c.205G>C) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-16). AlphaMissense: likely benign (0.1113); Ultra-rare (popmax 0.0165%, sas).

How common is TH p.Glu69Gln (c.205G>C) in the general population?

TH p.Glu69Gln (c.205G>C) is ultra-rare (popmax 0.0165%, sas) (gnomAD).

What do computational predictors say about TH p.Glu69Gln (c.205G>C)?

AlphaMissense predicts likely benign (score 0.1113) — an in-silico prediction, not a clinical call.

TH p.Glu69Gln

c.205G>C · VCV3770033

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1113 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1113	likely benign
REVEL	0.491	indeterminate
SaProt	LLR -8.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 0.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	16.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM E100Q vs ClinVar E69Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% South Asian · 15/91,058 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00093% 15/1,612,256 alleles · ultra-rare exomes 14/1,460,054 · genomes 1/152,202 · joint denominator

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.Glu69Gln
Coding: c.205G>C
MANE Select: NM_000360
Type: single nucleotide variant
Location: chr11:2169757 (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

Similar variants

TH p.Glu69Lys Uncertain significance ★ ⚠ same residue
TH p.Glu69= Likely benign ★ same residue
TH p.Glu69fs Likely pathogenic ★ same residue
TH c.1200+2T>C Likely pathogenic ★★ same type
TH c.1334+1G>A Likely pathogenic ★★ same type
TH c.312+1G>A Likely pathogenic ★★ same type
TH c.488-1G>A Pathogenic ★★ same type
TH c.644+1G>A Likely pathogenic ★★ same type

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-glu69gln (accessed [today's date]).

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