Is TNIK p.Pro21= (c.63C>T) pathogenic?

TNIK p.Pro21= (c.63C>T) is classified Benign in TNIK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-09-10). Common (popmax 75%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with intellectual disability, autosomal recessive 54.

What condition is associated with TNIK p.Pro21= (c.63C>T)?

TNIK p.Pro21= (c.63C>T) is associated with intellectual disability, autosomal recessive 54 (ClinVar).

TNIK p.Pro21=

Q: How common is TNIK p.Pro21= (c.63C>T) in the general population?

TNIK p.Pro21= (c.63C>T) is common (popmax 75%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.63C>T · rs3796295 · VCV1342236

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 75%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

intellectual disability, autosomal recessive 54

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.91	GERP -4.5, phastCons 0.99
Overall
CADD	8.727	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 75% European (non-Finnish) · 864,482/1,151,990 alleles

Filtering AF 74.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 74.9%

Overall 69.4% 1,084,448/1,562,586 alleles · common exomes 999,560/1,410,562 · genomes 84,888/152,024 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	77.4%	1
European (non-Finnish)grpmax	75%	1
Finnishnot grpmax-eligible	67.9%	1
Admixed American	67%	1
Remaining individualsnot grpmax-eligible	66.5%	2
Ashkenazi Jewishnot grpmax-eligible	64.2%	2
Middle Eastern	57.9%	2
South Asian	57.5%	2
East Asian	45%	2
African / African-American	17.1%	6

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TNIK
Protein: p.Pro21=
Coding: c.63C>T
MANE Select: NM_015028
dbSNP: rs3796295
Type: single nucleotide variant
Location: chr3:171369680 (GRCh38)
Gene constraint: LOEUF 0.338 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.60 · 12 PDB

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

Disease context

intellectual disability, autosomal recessive 54 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TNIK p.Arg545Trp Uncertain significance ★★ ⚠ same condition
TNIK p.Arg632Cys Uncertain significance ★★ ⚠ same condition
TNIK p.Arg914Gln Uncertain significance ★★ ⚠ same condition
TNIK p.Asn1353Ser Uncertain significance ★★ ⚠ same condition
TNIK p.Gly910Glu Uncertain significance ★★ ⚠ same condition
TNIK p.Lys913Gln Uncertain significance ★★ ⚠ same condition
TNIK c.1419+19A>G Benign ★★ same condition
TNIK p.Ala777= Benign ★★ 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/tnik-p-pro21 (accessed [today's date]).

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