Is PTK2B p.Met26Val (c.76A>G) pathogenic?

PTK2B p.Met26Val (c.76A>G) is classified Uncertain significance in PTK2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.056); Ultra-rare (popmax 0.0117%, amr).

How common is PTK2B p.Met26Val (c.76A>G) in the general population?

PTK2B p.Met26Val (c.76A>G) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about PTK2B p.Met26Val (c.76A>G)?

AlphaMissense predicts likely benign (score 0.056) — an in-silico prediction, not a clinical call.

PTK2B p.Met26Val

c.76A>G · VCV4147248

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.056 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.056	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -4.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.44, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 61 kb · p 3.1e-09 · regional, not allelic
Overall
CADD	15.82	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 0.0117% Admixed American · 7/60,024 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000619% 10/1,614,260 alleles · ultra-rare exomes 10/1,461,892 · genomes 0/152,368 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,575
South Asian	0.0011%	91,086
European (non-Finnish)	0.000169%	590,023

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: PTK2B
Protein: p.Met26Val
Coding: c.76A>G
MANE Select: NM_173176
Type: single nucleotide variant
Location: chr8:27397660 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 26 PDB
Residue 26: an α-helix

Full PTK2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PTK2B p.Met26Thr Uncertain significance ★ ⚠ same residue
PTK2B p.Gln359Glu Likely benign ★★ same type
PTK2B p.Leu178= Benign ★★ same type
PTK2B p.Pro413= Benign ★★ same type
PTK2B p.Thr264Asn Likely benign ★★ same type
PTK2B p.Ala258Thr Uncertain significance ★ ⚠ same type
PTK2B p.Ala345Thr Uncertain significance ★ ⚠ same type
PTK2B p.Ala709Val 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/ptk2b-p-met26val (accessed [today's date]).

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