Is PTK2 p.Arg709Ser (c.2127G>T) pathogenic?

PTK2 p.Arg709Ser (c.2127G>T) is classified Uncertain significance in PTK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.6018); Very rare (popmax 0.00134%, afr).

How common is PTK2 p.Arg709Ser (c.2127G>T) in the general population?

PTK2 p.Arg709Ser (c.2127G>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about PTK2 p.Arg709Ser (c.2127G>T)?

AlphaMissense predicts likely pathogenic (score 0.6018) — an in-silico prediction, not a clinical call.

PTK2 p.Arg709Ser

c.2127G>T · VCV4147242

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6018 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6018	likely pathogenic
REVEL	0.312	indeterminate
SaProt	LLR -9.52	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -0.33, phastCons 1
Overall
CADD	22.1	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 R668S vs ClinVar R709S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,886 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,886 alleles · very rare exomes 2/1,461,762 · genomes 1/152,124 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,886
European (non-Finnish)	0.000169%	590,005

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: PTK2
Protein: p.Arg709Ser
Coding: c.2127G>T
MANE Select: NM_001352702
Type: single nucleotide variant
Location: chr8:140735277 (GRCh38)
Gene constraint: LOEUF 0.399 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.10 · 40 PDB
Residue 668 UniProt numbering: the protein kinase domain

Full PTK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PTK2 p.Arg855Ter Uncertain significance ★★ same type
PTK2 c.*705T>A Benign ★★ same type
PTK2 p.Arg349= Benign ★★ same type
PTK2 p.Asp703= Benign ★★ same type
PTK2 p.Glu870= Benign/Likely benign ★★ same type
PTK2 p.Pro690= Benign ★★ same type
PTK2 p.Ser355= Benign ★★ same type
PTK2 p.Tyr969= Benign ★★ 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/ptk2-p-arg709ser (accessed [today's date]).

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