Is TH p.Ser157Arg (c.471C>G) pathogenic?

TH p.Ser157Arg (c.471C>G) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-08). AlphaMissense: ambiguous (0.3742); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with TH p.Ser157Arg (c.471C>G)?

TH p.Ser157Arg (c.471C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TH p.Ser157Arg (c.471C>G) in the general population?

TH p.Ser157Arg (c.471C>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about TH p.Ser157Arg (c.471C>G)?

AlphaMissense predicts ambiguous (score 0.3742) — an in-silico prediction, not a clinical call.

TH p.Ser157Arg

c.471C>G · VCV4183789

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3742	ambiguous
REVEL	0.246	benign-leaning
SaProt	LLR -6.57	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.9	GERP -2.2
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	3.497	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 S188R vs ClinVar S157R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,988 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,612,224 alleles · very rare exomes 2/1,460,084 · genomes 1/152,140 · 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.Ser157Arg
Coding: c.471C>G
MANE Select: NM_000360
Type: single nucleotide variant
Location: chr11:2168507 (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

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TH p.Ala317Gly Uncertain significance ★★ ⚠ same condition
TH p.Ala492Val Uncertain significance ★★ ⚠ same condition
TH p.Ala56Val Uncertain significance ★★ ⚠ same condition
TH p.Ala95Glu 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-ser157arg (accessed [today's date]).

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