Is TTC21B p.Pro463= (c.1389T>G) pathogenic?

TTC21B p.Pro463= (c.1389T>G) is classified Likely benign in TTC21B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-24). Very rare (popmax 0.00133%, afr); Associated with nephronophthisis.

What condition is associated with TTC21B p.Pro463= (c.1389T>G)?

TTC21B p.Pro463= (c.1389T>G) is associated with nephronophthisis, Jeune syndrome (ClinVar).

How common is TTC21B p.Pro463= (c.1389T>G) in the general population?

TTC21B p.Pro463= (c.1389T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

TTC21B p.Pro463=

c.1389T>G · rs1472298358 · VCV1973100

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.5	GERP -0.9, phastCons 1
Overall
CADD	11.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,908 alleles

Overall 6.2e-05% 1/1,613,186 alleles · very rare exomes 0/1,460,970 · genomes 1/152,216 · 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: TTC21B
Protein: p.Pro463=
Coding: c.1389T>G
MANE Select: NM_024753
dbSNP: rs1472298358
Type: single nucleotide variant
Location: chr2:165924676 (GRCh38)
Gene constraint: LOEUF 0.831 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.39 · 3 PDB
Residue 463: a UniProt-annotated variant site (in)

Full TTC21B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Jeune syndrome

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

TTC21B p.Pro463Ser Benign/Likely benign ★★ same residue
TTC21B c.1087+1G>A Likely pathogenic ★★ same condition
TTC21B c.1088-1G>A Pathogenic/Likely pathogenic ★★ same condition
TTC21B c.1386+1G>T Likely pathogenic ★★ same condition
TTC21B c.2758-2A>G Pathogenic/Likely pathogenic ★★ same condition
TTC21B c.2868+1G>T Likely pathogenic ★★ same condition
TTC21B c.2951-1G>A Likely pathogenic ★★ same condition
TTC21B c.3102-2A>G Likely pathogenic ★★ 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/ttc21b-p-pro463 (accessed [today's date]).

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