Is TH p.Ala58Val (c.173C>T) pathogenic?

TH p.Ala58Val (c.173C>T) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-22). AlphaMissense: likely benign (0.1284); Ultra-rare (popmax 0.0242%, sas); Associated with Inborn genetic diseases.

What condition is associated with TH p.Ala58Val (c.173C>T)?

TH p.Ala58Val (c.173C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TH p.Ala58Val (c.173C>T) in the general population?

TH p.Ala58Val (c.173C>T) is ultra-rare (popmax 0.0242%, sas) (gnomAD).

What do computational predictors say about TH p.Ala58Val (c.173C>T)?

AlphaMissense predicts likely benign (score 0.1284) — an in-silico prediction, not a clinical call.

TH p.Ala58Val

c.173C>T · rs747136659 · VCV3176816

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1284 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1284	likely benign
REVEL	0.397	indeterminate
SaProt	LLR -9.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 0.54, phastCons 0.76
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	15.83	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 A89V vs ClinVar A58V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0242% South Asian · 22/91,016 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00137% 22/1,611,038 alleles · ultra-rare exomes 20/1,458,738 · genomes 2/152,300 · 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.Ala58Val
Coding: c.173C>T
MANE Select: NM_000360
dbSNP: rs747136659
Type: single nucleotide variant
Location: chr11:2169789 (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.Ala58Asp Uncertain significance ★ ⚠ same residue
TH p.Ala58Thr Uncertain significance ★ ⚠ same residue
TH p.Ala58= Likely 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

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-ala58val (accessed [today's date]).

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