Is TNK1 p.Val593Met (c.1777G>A) pathogenic?

TNK1 p.Val593Met (c.1777G>A) is classified Benign in TNK1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-17). AlphaMissense: likely benign (0.2334); Common (popmax 95.1%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with TNK1-related disorder.

What condition is associated with TNK1 p.Val593Met (c.1777G>A)?

TNK1 p.Val593Met (c.1777G>A) is associated with TNK1-related disorder (ClinVar).

What do computational predictors say about TNK1 p.Val593Met (c.1777G>A)?

AlphaMissense predicts likely benign (score 0.2334) — an in-silico prediction, not a clinical call.

TNK1 p.Val593Met

Q: How common is TNK1 p.Val593Met (c.1777G>A) in the general population?

TNK1 p.Val593Met (c.1777G>A) is common (popmax 95.1%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1777G>A · rs6503018 · VCV3060054

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2334 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 95.1%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TNK1-related disorder

Computational evidence

Protein change
AlphaMissense	0.2334	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -11.68	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.038, phastCons 1
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V598M vs ClinVar V593M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 95.1% European (non-Finnish) · 1,117,902/1,175,980 alleles

Filtering AF 94.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 94.9%

Overall 90.6% 1,454,623/1,605,486 alleles · common exomes 1,332,945/1,453,368 · genomes 121,678/152,118 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	98.9%	1
Ashkenazi Jewishnot grpmax-eligible	97.8%	1
European (non-Finnish)grpmax	95.1%	1
Middle Eastern	92.6%	1
Remaining individualsnot grpmax-eligible	89.2%	1
Finnishnot grpmax-eligible	87.5%	1
South Asian	82%	1
Admixed American	77.9%	1
East Asian	73.1%	1
African / African-American	51.9%	2

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: TNK1
Protein: p.Val593Met
Coding: c.1777G>A
MANE Select: NM_003985
dbSNP: rs6503018
Type: single nucleotide variant
Location: chr17:7388788 (GRCh38)
Gene constraint: LOEUF 1.139 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.01 · 10 PDB
Residue 598 UniProt numbering: a UniProt-annotated variant site (in); an α-helix

Full TNK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TNK1-related disorder

Similar variants

TNK1 c.1398-2A>G Benign same condition
TNK1 p.Ala212= Likely benign same condition
TNK1 p.Ala299Asp Likely benign same condition
TNK1 p.Arg456Gln Benign same condition
TNK1 p.Asp47= Likely benign same condition
TNK1 p.Gly395= Benign same condition
TNK1 p.Leu27= Benign same condition
TNK1 p.Pro478= 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/tnk1-p-val593met (accessed [today's date]).

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