Is TH p.Arg277fs (c.829del) pathogenic?

TH p.Arg277fs (c.829del) is classified Likely pathogenic in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-17). Very rare (popmax 0.00112%, sas); Associated with Bietti crystalline corneoretinal dystrophy.

What condition is associated with TH p.Arg277fs (c.829del)?

TH p.Arg277fs (c.829del) is associated with Bietti crystalline corneoretinal dystrophy (ClinVar).

How common is TH p.Arg277fs (c.829del) in the general population?

TH p.Arg277fs (c.829del) is very rare (popmax 0.00112%, sas) (gnomAD).

How is Bietti crystalline dystrophy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TH p.Arg277fs

c.829del · VCV4850354

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00112%, sas)

Conditions

Bietti crystalline corneoretinal dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2	GERP -3.7, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00112% South Asian · 1/89,336 alleles

Overall 6.23e-05% 1/1,604,936 alleles · very rare exomes 0/1,452,708 · genomes 1/152,228 · 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.Arg277fs
Coding: c.829del
MANE Select: NM_000360
Type: Deletion
Location: chr11:2166899 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 277: an α-helix

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

Disease context

Bietti crystalline corneoretinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Bietti crystalline dystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult

Similar variants

TH p.Arg277Ser Uncertain significance ★ ⚠ same residue
TH p.Arg277= Likely benign ★ same residue
TH p.Gln346fs Pathogenic/Likely pathogenic ★★ same type
TH p.Glu375fs Pathogenic/Likely pathogenic ★★ same type
TH p.His335fs Likely pathogenic ★★ same type
TH p.Ser195fs Pathogenic/Likely pathogenic ★★ same type
TH p.Ser404fs Pathogenic/Likely pathogenic ★★ same type
TH p.Thr238fs Pathogenic/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-arg277fs (accessed [today's date]).

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