Is TNIK p.Ala998Pro (c.2992G>C) pathogenic?

TNIK p.Ala998Pro (c.2992G>C) is classified Uncertain significance in TNIK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-14). AlphaMissense: likely benign (0.1243); Very rare (popmax 0.00068%, nfe).

How common is TNIK p.Ala998Pro (c.2992G>C) in the general population?

TNIK p.Ala998Pro (c.2992G>C) is very rare (popmax 0.00068%, nfe) (gnomAD).

What do computational predictors say about TNIK p.Ala998Pro (c.2992G>C)?

AlphaMissense predicts likely benign (score 0.1243) — an in-silico prediction, not a clinical call.

TNIK p.Ala998Pro

c.2992G>C · VCV3459245

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1243 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00068%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1243	likely benign
REVEL	0.317	indeterminate
SaProt	LLR -6.45	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 73 kb · p 0.0001 · regional, not allelic
Overall
CADD	23.4	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00068% European (non-Finnish) · 8/1,176,580 alleles

Filtering AF 0.000293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000498% 8/1,606,826 alleles · very rare exomes 5/1,454,656 · genomes 3/152,170 · 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: TNIK
Protein: p.Ala998Pro
Coding: c.2992G>C
MANE Select: NM_015028
Type: single nucleotide variant
Location: chr3:171085124 (GRCh38)
Gene constraint: LOEUF 0.338 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.60 · 12 PDB
Residue 998: the 'disordered' region; the 'mediates interaction with nedd4' region

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

Similar variants

TNIK p.Ala998= Likely benign ★★ same residue
TNIK p.Ala998Thr Uncertain significance ★ ⚠ same residue
TNIK p.Arg545Trp Uncertain significance ★★ ⚠ same type
TNIK p.Arg632Cys Uncertain significance ★★ ⚠ same type
TNIK p.Arg914Gln Uncertain significance ★★ ⚠ same type
TNIK p.Asn1353Ser Uncertain significance ★★ ⚠ same type
TNIK p.Gly910Glu Uncertain significance ★★ ⚠ same type
TNIK p.Ile653Phe Uncertain significance ★★ ⚠ 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/tnik-p-ala998pro (accessed [today's date]).

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