Is TH p.Ala210Val (c.629C>T) pathogenic?

TH p.Ala210Val (c.629C>T) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-29). AlphaMissense: likely pathogenic (0.9647); Ultra-rare (popmax 0.0165%, mid).

How common is TH p.Ala210Val (c.629C>T) in the general population?

TH p.Ala210Val (c.629C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about TH p.Ala210Val (c.629C>T)?

AlphaMissense predicts likely pathogenic (score 0.9647) — an in-silico prediction, not a clinical call.

TH p.Ala210Val

c.629C>T · rs752390068 · VCV3251358

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9647 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9647	likely pathogenic
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -11.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 A241V vs ClinVar A210V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,052 alleles

Overall 6.22e-05% 1/1,608,454 alleles · ultra-rare exomes 1/1,456,128 · genomes 0/152,326 · 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.Ala210Val
Coding: c.629C>T
MANE Select: NM_000360
dbSNP: rs752390068
Type: single nucleotide variant
Location: chr11:2167881 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 241 UniProt numbering: a UniProt-annotated variant site (in arsegs; loss of over 80% of tyrosine 3-monooxygenase activity); an α-helix

Full TH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TH p.Ala210Thr Pathogenic/Likely pathogenic ★★ same residue
TH p.Ala210Ser Uncertain significance ★★ ⚠ same residue
TH p.Ala210Gly Uncertain significance ★ ⚠ same residue
TH p.Ala210= Likely benign ★ 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

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-ala210val (accessed [today's date]).

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